Animal and human anti-trypanosomonal and anti-leishmania agents

ABSTRACT

Provided herein are Aminopurine compounds of Formula I: 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof, wherein R 1 , R 2 , and R 3  are as defined herein, compositions comprising an effective amount of an Aminopurine Compound, and methods for treating or preventing animal and human protozoal infections.

This application is a divisional of U.S. patent application Ser. No.15/611,061, filed Jun. 1, 2017, currently allowed, which claims thebenefit of U.S. Provisional Application No. 62/344,759, filed Jun. 2,2016, the entire contents of which is incorporated herein by reference.

FIELD

Provided herein are certain aminopurine compounds, compositionscomprising an effective amount of such compounds, and methods fortreating or preventing trypanosomosis, trypanosomiasis, orleishmaniasis, comprising administering an effective amount of suchaminopurine compounds to a subject in need thereof. Accordingly, alsoprovided herein are such compounds for use in said methods for treatingor preventing trypanosomosis, trypanosomiasis, or leishmaniasis.

BACKGROUND

Protozoa of the genus Trypanosoma and Leishmania are known to cause anumber of diseases in animals and humans. These protozoa can betransmitted by blood feeding invertebrates, by mechanical vectors orvenereally, and are responsible for a number of diseases known astrypanosomosis or trypanosomiasis and leishmaniasis. Animal AfricanTrypanosomosis (AAT), Human African Trypanosomiasis (HAT), Chagasdisease and leishmaniasis are such parasitic diseases, which result insignificant morbidity and mortality.

Animal trypanosomosis or African animal trypanosomosis (AAT) is one ofthe most significant infectious threats to cattle and other livestock insub-Saharan Africa, and it also is also widespread in Asia and SouthAmerica. African animal trypanosomosis (AAT) remains one of the biggestinfectious disease constraints to productive livestock rearing insub-Saharan Africa. AAT is also becoming increasingly prevalent beyondthis region and is an established threat to animal health in SouthAmerica and Asia. Trypanosomes are spread by the bite of infected tsetseflies (Glossina species). Certain Trypanoxome species can bemechanically transmitted by biting flies or by venereal transmission.Animal trypanosomosis clinical symptoms vary from per-acute to chronicand include intermittent fever, anaemia, weight loss, hypertrophy oflymph nodes, oedema, hemorrhages, rough hair coat, lacrimation,abortion, sterility, and reduction in draught power. Death often followsin animals not treated effectively. There are veterinary trypanocidaldrugs, based on several families of compounds, however, most weredeveloped more than 50 years ago, that are used for treatment andchemoprophylaxis. Widespread resistance is reported against theavailable trypanocidal drugs. Many of the current drugs for animaltrypanosomosis have poor therapeutic indices and there are concernsabout their human safety (meat and milk residues and exposure ofadministrators to the drug). All of these current therapies havedeficiencies, including resistance and safety, and new trypanocidalagents are urgently needed.

Human African trypanosomiasis (HAT), also known as sleeping sickness, istransmitted by the tsetse fly (Glossina genus) which have acquired theirinfection from human beings or from animals harboring the humanpathogenic parasites. In the early stages of HAT, the trypanosomesmultiply in subcutaneous tissues, blood and lymph. This is also calledthe hemo-lymphatic stage, which produces bouts of fever, headaches,joint pains and itching. In the advanced stage of HAT, the parasitescross the blood-brain barrier to infect the central nervous system,known as the neurological or meningo-encephalic stage. Symptoms includechanges of behavior, confusion, sensory disturbances, poor coordinationand sleep disturbances. Without treatment, sleeping sickness isconsidered fatal. Several drugs are used to treat the early and advancedstages of HAT, however, the treatments are marred by toxicities(including fatalities), complex and difficult administration, lowresponse rates, resistance and narrow therapeutic indices.

A different form of human trypanosomiasis occurs mainly in Latin Americaand is known as American trypanosomiasis or Chagas disease, caused bythe T. cruzi trypanosome species. Chagas is vector-borne by contact withfeces or urine of blood-sucking triatomine bugs (insects), known askissing bugs. Chagas disease occurs mainly in the continental part ofLatin America, but has been increasingly detected in the United States,Canada, and many European and some Western Pacific countries. Chagasdisease presents itself in two phases. The initial, acute phase lastsfor about 2 months after infection. During the acute phase, a highnumber of parasites circulate in the blood but in most cases symptomsare absent or mild. In less than 50% of people bitten by a triatominebug, characteristic first visible signs may be a skin lesion or apurplish swelling of the lids of one eye. Additionally patients maypresent with fever, headache, enlarged lymph glands, pallor, musclepain, difficulty in breathing, swelling, and abdominal or chest pain.During the chronic phase, the parasites are hidden mainly in the heartand digestive muscles. Up to 30% of patients suffer from cardiacdisorders and up to 10% suffer from digestive (typically enlargement ofthe esophagus or colon), neurological or mixed alterations. In lateryears the infection may lead to sudden death or heart failure caused byprogressive destruction of the heart muscle and the nervous system.Chagas disease can be treated with benznidazole and also nifurtimox.Both medicines are effective in curing the disease if given soon afterinfection at the onset of the acute phase including the cases ofcongenital transmission. The efficacy of both drugs diminishes, however,the longer a person has been infected.

Leishmaniasis is a disease caused by protozoa of the genus Leishmania.Primary hosts are mammals, including human and rodents. Typically,Leishmaniasis results from Leishmania transmission by the bite ofcertain species of sand fly (e.g. Phiebotominae and Lutzomyi). The humandisease is zoonotic (i.e transmissible from non-human animals), but somecan be spread between humans. There are three main forms ofleishmaniases—visceral (the most serious form of the disease), cutaneous(the most common), and mucocutaneous. Visceral leishmaniasis (VL; causedby L. donovani), also known as kala-azar is fatal if left untreated inover 95% of cases. It is characterized by irregular bouts of fever,weight loss, enlargement of the spleen and liver, and anemia. It ishighly endemic in the Indian subcontinent and in East Africa. Anestimated 200,000 to 400,000 new cases of VL occur worldwide each year.Over 90% of new cases occur in six countries: Bangladesh, Brazil,Ethiopia, India, South Sudan and Sudan. Post-kala-azar dermalleishmaniasis (PKDL) is a sequel of visceral leishmaniasis that appearsas macular, papular or nodular rash usually on face, upper arms, trunksand other parts of the body. It occurs mainly in East Africa and theIndian subcontinent. It usually appears 6 months to 1 or more yearsafter kala-azar has apparently been cured, but may occur earlier. Peoplewith PKDL are considered to be a potential source of kala-azarinfection. Cutaneous leishmaniasis (CL) is the most common form ofleishmaniasis and causes skin lesions, mainly ulcers, on exposed partsof the body, leaving life-long scars and serious disability. About 95%of CL cases occur in the Americas, the Mediterranean basin, the MiddleEast and Central Asia. Over two thirds of new CL cases occur in 6countries: Afghanistan, Algeria, Brazil, Colombia, Iran and the SyrianArab Republic. Mucocutaneous leishmaniasis leads to partial or totaldestruction of mucous membranes of the nose, mouth and throat. Almost90% of mucocutaneous leishmaniasis cases occur in Bolivia, Brazil andPeru. The current treatments suffer from safety/toxicity concerns(including cardiotoxicty), incomplete cure rates, difficultadministration, long duration of treatment, lack of compliance anddeveloping resistance. (Disease descriptions and facts were obtainedfrom www.who.org).

Consequently, there remains a need to develop effective therapeuticagents for the infectious diseases and their symptoms described above.

Citation or identification of any reference in this application is notto be construed as an admission that the reference is prior art to thepresent application.

SUMMARY

Provided herein are Aminopurine Compounds of formula (I)

wherein R¹, R² and R³ are as defined herein.

In one aspect, provided herein are Aminopurine Compounds as described inthe instant disclosure, such as, for example, an Aminopurine Compound offormula (I), or a compound from Table 1 or Table 2.

In one aspect, provided herein are pharmaceutical compositionscomprising an effective amount of an Aminopurine Compound, as describedherein, and a pharmaceutically acceptable carrier, excipient or vehicle.In some embodiments the pharmaceutical composition is suitable for oral,parenteral, mucosal, transdermal or topical administration.

In one aspect, provided herein are uses of Aminopurine Compounds fortreating or preventing trypanosomosis, trypanosomiasis, and/orleishmaniasis, wherein the methods comprise administering to a subjectin need thereof an effective amount of an Aminopurine Compound asdescribed herein. In another aspect, provided herein are uses ofAminopurine Compounds for treating or preventing trypanosomosis,trypanosomiasis, and/or leishmaniasis, wherein the methods compriseadministering to a subject in need thereof an effective amount of anAminopurine Compound as described herein.

In one aspect, provided herein is an Aminopurine Compound for use as amedicament. Provided is the Aminopurine Compound for use in a method forthe treatment or prevention of trypanosomosis, trypanosomiasis, orleishmaniasis, the method comprising administering to a subject in needthereof an effective amount of the Aminopurine Compound. Provided hereinis an Aminopurine Compound for use in a method of treating or preventingAnimal trypanosomosis or African animal trypanosomosis (AAT), the methodcomprising administering to a subject in need thereof an effectiveamount of the Aminopurine Compound. Provided herein is an AminopurineCompound for use in a method of treating or preventing Human Africantrypanosomiasis (HAT), comprising administering to a subject in needthereof an effective amount of the Aminopurine Compound. Provided hereinis an Aminopurine Compound for use in a method of treating or preventingAmerican trypanosomiasis or Chagas disease, comprising administering toa subject in need thereof an effective amount of the AminopurineCompound. Provided herein is an Aminopurine Compound for use in a methodof treating or preventing Leishmaniasis, comprising administering to asubject in need thereof an effective amount of the Aminopurine Compound.

In another aspect provided herein are methods for preparing AminopurineCompounds as described herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

DETAILED DESCRIPTION Definitions

As used herein, the terms “comprising” and “including” can be usedinterchangeably. The terms “comprising” and “including” are to beinterpreted as specifying the presence of the stated features orcomponents as referred to, but does not preclude the presence oraddition of one or more features, or components, or groups thereof.Additionally, the terms “comprising” and “including” are intended toinclude examples encompassed by the term “consisting of”. Consequently,the term “consisting of” can be used in place of the terms “comprising”and “including” to provide for more specific embodiments of theinvention.

The term “consisting of” means that a subject-matter has at least 90%,95%, 97%, 98% or 99% of the stated features or components of which itconsists. In another embodiment the term “consisting of” excludes fromthe scope of any succeeding recitation any other features or components,excepting those that are not essential to the technical effect to beachieved.

As used herein, the term “or” is to be interpreted as an inclusive “or”meaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl,-2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyland the like. Examples of unsaturated alkyl groups include, but are notlimited to, vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)=CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃) and —CH₂C≡C(CH₂CH₃), among others. An alkyl groupcan be substituted or unsubstituted. When the alkyl groups describedherein are said to be “substituted,” they may be substituted with anysubstituent or substituents as those found in the exemplary compoundsand embodiments disclosed herein, as well as halogen (chloro, iodo,bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino;alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide;amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate;phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone;aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine;aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)₂, orO(alkyl)aminocarbonyl.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substitutedwith from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl grouphas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like.Examples of unsaturared cycloalkyl groups include cyclohexenyl,cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl,among others. A cycloalkyl group can be substituted or unsubstituted.Such substituted cycloalkyl groups include, by way of example,cyclohexanol and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl(e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl,pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl(e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridylor 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl),tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocycloalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl)groups. The phrase heterocyclyl includes fused ring species, includingthose comprising fused aromatic and non-aromatic groups, such as, forexample, 1- and 2-aminotetraline, benzotriazolyl (e.g.,1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, andbenzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ringsystems containing a heteroatom such as, but not limited to,quinuclidyl. Representative examples of a heterocyclyl group include,but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl,pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl orimidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g.,benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl),morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g.,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g.,indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl,isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl),indazolyl, indolizinyl, benzotriazolyl (e.g.1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl,benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl,benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl (for example,1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl(e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl,isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one andtetrahydroquinolinyl groups. Representative non-aromatic heterocyclylgroups do not include fused ring species that comprise a fused aromaticgroup. Examples of non-aromatic heterocyclyl groups include aziridinyl,azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g.,imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl,piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl,tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl,oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl,quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representativesubstituted heterocyclyl groups may be mono-substituted or substitutedmore than once, such as, but not limited to, pyridyl or morpholinylgroups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstitutedwith various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tomethylcyclopropyl, methylcyclobutyl, methylcyclopentyl,methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl,ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl and the like.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

An “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyridin-3-yl methyl, tetrahydrofuran-2-yl ethyl, andindol-2-yl propyl.

A “halogen” is fluorine, chlorine, bromine or iodine.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amino” group is a radical of the formula: —NH₂.

An “alkylamino” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

A “carboxy” group is a radical of the formula: —C(O)OH.

An “aminocarbonyl” group is a radical of the formula: —C(O)N(R#)₂,—C(O)NH(R^(#)) or —C(O)NH₂, wherein each R^(#) is independently asubstituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl or heterocyclyl group as defined herein.

An “acylamino” group is a radical of the formula: —NHC(O)(R^(#)) or—N(alkyl)C(O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(O)N(R^(#))₂,—N(alkyl)C(O)NH(R^(#)), —N(alkyl)C(O)NH₂, —NHC(O)N(R^(#))₂,—NHC(O)NH(R^(#)), or —NH(CO)NHR#, wherein each alkyl and R^(#) areindependently as defined above.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl,piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fusedor non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl,benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy;heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “Aminopurine Compound” refers to compounds offormula (I) as well as to further embodiments of compounds of formula(I) provided herein. For example, the term “Aminopurine Compound” refersto deuterated compounds of formula (I). In one embodiment, an“Aminopurine Compound” is a compound set forth in Table 1 or Table 2. Incertain embodiments, the term “Aminopurine Compound” includespharmaceutically acceptable salts, tautomers, isotopologues, and/orstereoisomers of the Aminopurine Compounds provided herein.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of thecompounds of formula (I) include, but are not limited to metallic saltsmade from aluminum, calcium, lithium, magnesium, potassium, sodium andzinc or organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methyl-glucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples ofspecific salts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of an AminopurineCompound that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The AminopurineCompounds can have chiral centers and can occur as racemates, individualenantiomers or diastereomers, and mixtures thereof. All such isomericforms are included within the embodiments disclosed herein, includingmixtures thereof.

The use of stereomerically pure forms of such Aminopurine Compounds, aswell as the use of mixtures of those forms, are encompassed by theembodiments disclosed herein. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular Aminopurine Compoundmay be used in methods and compositions disclosed herein. These isomersmay be asymmetrically synthesized or resolved using standard techniquessuch as chiral columns or chiral resolving agents. See, e.g., Jacques,J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience,New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind., 1972).

It should also be noted the Aminopurine Compounds can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the Aminopurine Compounds are isolatedas either the E or Z isomer. In other embodiments, the AminopurineCompounds are a mixture of the E and Z isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of compounds of formula (I) are within the scope of thepresent invention.

It should also be noted the Aminopurine Compounds can contain unnaturalproportions of atomic isotopes at least one of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I) sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with carbon-13 (¹³C), ornitrogen-15 (¹⁵N). As used herein, an “isotopologue” is an isotopicallyenriched compound. The term “isotopically enriched” refers to an atomhaving an isotopic composition other than the natural isotopiccomposition of that atom. “Isotopically enriched” may also refer to acompound containing at least one atom having an isotopic compositionother than the natural isotopic composition of that atom. The term“isotopic composition” refers to the amount of each isotope present fora given atom. Radiolabeled and isotopically enriched compounds areuseful as therapeutic agents, e.g., cancer and inflammation therapeuticagents, research reagents, e.g., binding assay reagents, and diagnosticagents, e.g., in vivo imaging agents. All isotopic variations of theAminopurine Compounds as described herein, whether radioactive or not,are intended to be encompassed within the scope of the embodimentsprovided herein. In some embodiments, there are provided isotopologuesof the Aminopurine Compounds, for example, the isotopologues arecarbon-13, or nitrogen-15 enriched Aminopurine Compounds. As usedherein, “deuterated”, means a compound wherein at least one hydrogen (H)has been replaced by deuterium (indicated by D or ²H), that is, thecompound is enriched in deuterium in at least one position.

It should be noted that if there is a discrepancy between a depictedstructure and a name for that structure, the depicted structure is to beaccorded more weight.

As used herein, “inhibit” and “inhibition” mean that a specifiedresponse of a designated activity (e.g., parasite growth) iscomparatively decreased in the presence of an Aminopurine Compound.Inhibition of parasite growth, for example growth of T. congolensce, T.vivax and/or T. evansi, can be determined by the assays describedherein.

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition.

The term “effective amount” in connection with an Aminopurine Compoundmeans an amount capable of treating or preventing a disorder, disease orcondition, or symptoms thereof, disclosed herein.

The term “subject” or “patient” includes an animal, including, but notlimited to, an animal such a bull, camel, cat, cattle, chicken, cow,deer, dog, donkey, duck, elephant, gerbil, goat, goose, guinea fowl,guinea pig, honey bee, horse, ostrich, otter, pig, pigeon, rabbit,reindeer, sheep, swan, turkey, water buffalo, or yak, in one embodimenta mammal, in another embodiment a human, in another embodiment a cellfrom any one of the foregoing subjects. In one embodiment, a subject orpatient is a non-human animal. In another embodiment, a subject orpatient is a non-human mammal.

The term “combination” or administration “in combination” includesadministration as a mixture, simultaneous administration using separateformulations, and consecutive administration in any order.

The term “consecutive” means that more than 10 minutes have passedbetween the administration of the anti-MIF antibody and theadministration of the chemotherapeutic agent. The time period can thenbe more than 10 minutes, more than 30 minutes, more than 1 hour, morethan 3 hours, more than 6 hours or more than 12 hours.

In one embodiment, a subject or patient is a human having or at risk forhaving trypanosomiasis, and/or leishmaniasis. In some such embodiments,the subject or patient is a human having or at risk for havingleishmaniasis. In some such embodiments, the subject or patient is ahuman having or at risk for having Chagas Disease. In anotherembodiment, a subject is a bull, camel, cat, cattle, chicken, cow, deer,dog, donkey, duck, elephant, gerbil, goat, goose, guinea fowl, guineapig, honey bee, horse, ostrich, otter, pig, pigeon, rabbit, reindeer,sheep, swan, turkey, water buffalo, or yak having or at risk for havingtrypanosomosis. In another embodiment a subject is cattle, having or atrisk for having trypanosomosis.

Compounds

Provided herein are Aminopurine Compounds having the following formula(I):

wherein:

R¹ is CR^(1a)R^(1b)R^(1c), wherein each of R^(1a), R^(1b) and R^(1c) isindependently (C₁₋₄)alkyl, or (C₁₋₄)alkyl(OR); or R^(1a) and R^(1b) andthe carbon to which they are attached form a 3-6 membered cycloalkyl or3-6 membered heterocyclyl, and R^(1c) is (C₁₋₄)alkyl;

R² is cycloalkyl or aryl, substituted with at least one NR₂, OR, CN,NRC(O)R, CH₂OR, CH₂NR₂, CH₂NRCOR, CH₂NRCOOR′, or heterocyclylalkyl;

R³ is phenyl or pyridyl, optionally substituted with at least onehalogen, CN, (C₁₋₂)alkyl, or O(C₁₋₂)alkyl, wherein the alkyl isoptionally fluorinated;

R is H or (C₁₋₄) alkyl; and

R′ is (C₁₋₄)alkyl;

provided the Aminopurine Compound is not

-   4-(2-(tert-butylamino)-8-((2,6-difluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol

-   4-(2-(tert-butylamino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol

or

-   4-(2-(tert-butyl    amino)-8-((2,4-difluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol

In some embodiments of compounds of formula (I), R¹ isCR^(1a)R^(1b)R^(1c), wherein each of R^(1a), R^(1b) and R^(1c) isindependently (C₁₋₂)alkyl. For example, R¹ is t-butyl, C(CH₃)₂CH₂CH₃, orC(CH₃)₂CH₂OH. In other embodiment, R¹ is t-butyl. In other embodiment,R¹ is C(CH₃)₂CH₂CH₃. In other embodiment, R¹ is C(CH₃)₂CH₂OH. In otherembodiments of compounds of formula (I), R¹ is CR^(1a)R^(1b)R^(1c),wherein R^(1a) and R^(1b) and the carbon to which they are attached forma 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and R^(1c) is(C₁₋₄)alkyl. In some such embodiments, R^(1a) and R^(1b) and the carbonto which they are attached form a cyclopropyl, cyclobutyl, cyclohexyl,or tetrahydropyranyl. In some such embodiments, R^(1c) is CH₃. Forexample, R¹ is 1-methylcyclopropyl, 1-methylcyclobutyl,1-methylcyclpentyl, 1-methyl-tetrahydropyranyl,4-methyl-tetrahydropyranyl or 2,2-dimethyltetrahydropyranyl. In oneembodiment, R¹ is 1-methylcyclopropyl. In one embodiment, R¹ is1-methylcyclobutyl. In one embodiment, R¹ is 1-methylcyclpentyl. In oneembodiment, R¹ is 1-methyl-tetrahydropyranyl. In one embodiment, R¹ is4-methyl-tetrahydropyranyl. In a specific embodiment, R¹ is4-methyl-tetrahydropyran-4-yl. In one embodiment, R¹ is2,2-dimethyltetrahydropyranyl. In a specific embodiment, R¹ is2,2-dimethyltetrahydropyran-4-yl.

In some embodiments of compounds of formula (I), R² is (C₃₋₇)cycloalkyl,substituted with at least one NR₂, OR, CN, NRC(O)R, CH₂OR, CH₂NR₂,CH₂NRC(O)R, CH₂NRC(O)OR′ or heterocyclylalkyl. In some such embodiments,R² is cyclobutyl, cyclopentyl, or cyclohexyl. In some other suchembodiments, R² is substituted with at least one NH₂, NHCH₃, N(CH₃)₂,OH, OCH₃, CN, NHC(O)CH₃, N(CH₃)C(O)CH₃, CH₂OH, CH₂OCH₃, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NHC(O)CH₃, CH₂N(CH₃)C(O)CH₃, CH₂NHC(O)OCH₃,CH₂N(CH₃)C(O)OCH₃, CH₂-piperidyl, or CH₂-morpholinyl. In some suchembodiments, R² is cyclobutyl, substituted with NH₂. In someembodiments, R² is cyclohexyl, substituted with NH₂, OH, CN, NHC(O)CH₃,CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NHC(O)CH₃, CH₂NHC(O)OCH₃,CH₂-piperidyl, or CH₂-morpholinyl. In one embodiments, R² is cyclobutylsubstituted with NH₂. In one embodiment, R² is cyclohexyl, substitutedwith OH. In one embodiment, R² is cyclohexyl, substituted with CN,NHC(O)CH₃. In one embodiment, R² is cyclohexyl, substituted with CH₂OH.In one embodiment, R² is cyclohexyl, substituted with CH₂NH₂. In oneembodiment, R² is cyclohexyl, substituted with CH₂NHCH₃. In oneembodiment, R² is cyclohexyl, substituted with CH₂N(CH₃)₂. In oneembodiment, R² is cyclohexyl, substituted with CH₂NHC(O)CH₃. In oneembodiment, R² is cyclohexyl, substituted with CH₂NHC(O)OCH₃. In oneembodiment, R² is cyclohexyl, substituted with CH₂-piperidyl. In oneembodiment, R² is cyclohexyl, substituted with CH₂-morpholinyl. In yetother embodiments of compounds of formula (I), R² is aryl, substitutedwith at least one NR₂, OR, CN, NRC(O)R, CH₂OR, CH₂NR₂, CH₂NRCOR, orCH₂NRCOOR′. For example, R² is phenyl, substituted with at least oneNH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, CN, NHC(O)CH₃, N(CH₃)C(O)CH₃, CH₂OH,CH₂OCH₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NHC(O)CH₃, CH₂N(CH₃)C(O)CH₃,CH₂NHC(O)OCH₃, or CH₂N(CH₃)C(O)OCH₃. in some embodiments, R² is phenyl,substituted with CH₂NH₂.

In some embodiments of compounds of formula (I), R³ is phenyl,substituted with at least one halogen, fluorinated (C₁₋₂)alkyl, orO-fluorinated(C₁₋₂)alkyl. In some such embodiments, R³ is substitutedwith at least one F, Cl, CHF₂, CF₃, or OCF₃. In other such embodiments,R³ is meta-substituted phenyl, for example, R³ is meta-F-phenyl,meta-Cl-phenyl, meta-CF₃-phenyl, or meta-OCF₃-phenyl. In one embodiment,R³ is meta-F-phenyl. In one embodiment, R³ is meta-Cl-phenyl. In oneembodiment, R³ is meta-CF₃-phenyl. In one embodiment, R³ ismeta-OCF₃-phenyl. In still other embodiments, R³ is bis-meta-substitutedphenyl, wherein each substituent is independently F, Cl, or CF₃. In oneembodiment, R³ is bis-meta-substituted phenyl, wherein each substituentis F. In one embodiment, R³ is bis-meta-substituted phenyl, wherein eachsubstituent is Cl. In one embodiment, R³ is bis-meta-substituted phenyl,wherein one substituent is F and one substituent is Cl. In oneembodiment, R³ is bis-meta-substituted phenyl, wherein one substituentis F and one substituent is CF₃. In one embodiment, R³ isbis-meta-substituted phenyl, wherein one substituent is Cl and onesubstituent is CF₃. In some embodiments, R³ is para-substituted phenyl,for example, para-OCF₃-phenyl, para-CF₃-phenyl or para-Cl-phenyl. In oneembodiment, R³ is para-Cl-phenyl. In one embodiment, R³ ispara-CF₃-phenyl. In one embodiment, R³ is para-OCF₃-phenyl. In someembodiments, R³ is ortho-F, meta-CF₃-phenyl, ortho-F, meta-Cl-phenyl, ormeta-Cl, para-Cl-phenyl. In one embodiment, R³ is ortho-F,meta-F-phenyl. In one embodiment, R³ is ortho-F, meta-CF₃-phenyl. In oneembodiment, R³ is ortho-F, meta-Cl-phenyl. In one embodiment, R³ ismeta-Cl, para-Cl-phenyl. In some other embodiments of formula (I), R³ ispyridyl substituted with at least one halogen, fluorinated (C₁₋₂)alkyl,O-fluorinated(C₁₋₂)alkyl or CF₃. In one embodiment, R³ is pyridylsubstituted with Cl. In one embodiment, R³ is pyridyl substituted withCF₃. In some such embodiments, R³ is substituted with at least one F,Cl, CHF₂, CF₃, or OCF₃. In one embodiment, R³ is substituted with atleast one Cl, or CF₃.

In some embodiments of compounds of formula (I), wherein R¹ isCR^(1a)R^(1b)R^(1c), wherein R^(1a) and R^(1b) and the carbon to whichthey are attached form a 3-6 membered cycloalkyl or 3-6 memberedheterocyclyl, and R^(1c) is (C₁₋₄)alkyl, R² is cyclohexyl, substitutedwith NH₂, OH, CN, NHC(O)CH₃, CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂,CH₂NHC(O)CH₃, CH₂NHC(O)OCH₃, CH₂-piperidyl, or CH₂-morpholinyl. In somesuch embodiments, R³ is meta-substituted phenyl, or bis-meta-substitutedphenyl. In some such embodiments, R¹ is 1-methylcyclopropyl,1-methylcyclobutyl, 1-methylcyclpentyl or 1-methyl-tetrahydropyranyl. Inothers, R³ is meta-F-phenyl, meta-Cl-phenyl, meta-CF₃-phenyl, ormeta-OCF₃-phenyl, or R³ is bis-meta-substituted phenyl, wherein eachsubstituent is independently F, Cl, or CF₃.

Further embodiments provided herein include combinations of at least oneof the particular embodiments set forth above.

Representative compounds of formula (I) are set forth in Table 1.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-tert-pentyl-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine.

In one embodiment, the compound isN8-(3-chlorophenyl)-9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(pyridin-2-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(pyridin-2-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,

In one embodiment, the compound is(1s,4s)-4-(8-(3-chlorophenylamino)-2-(1-methylcyclopentylamino)-9H-purin-9-yl)cyclohexanol.

In one embodiment, the compound isN-(((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is methyl((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methylcarbamate.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-p-tolyl-9H-purine-2,8-diamine.

In one embodiment, the compound is((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol.

In one embodiment, the compound is9-((1R,3S)-3-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound isN8-(3-chlorophenyl)-9-((1s,4s)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is(1s,4s)-4-(2-(4-methyltetrahydro-2H-pyran-4-ylamino)-8- In oneembodiment, the compound is(3-(trifluoromethyl)phenylamino)-9H-purin-9-yl)cyclohexanecarbonitrile.

In one embodiment, the compound isN-((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)acetamide.

In one embodiment, the compound is((1r,4r)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol.

In one embodiment, the compound is9-((1s,4s)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-(4-(aminomethyl)phenyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(2-(trifluoromethyl)pyridin-4-yl)-9H-purine-2,8-diamine.

-   9-(3-aminocyclobutyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-(3-aminocyclobutyl)-N2-tert-butyl-N8-(3,4-dichlorophenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound isN8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1s,4s)-4-(piperidin-1-ylmethyl)cyclohexyl)-9H-purine-2,8-diamine.

In one embodiment, the compound isN8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1s,4s)-4-(morpholinomethyl)cyclohexyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopropyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is3-(9-((1r,4r)-4-aminocyclohexyl)-2-(tert-butylamino)-9H-purin-8-ylamino)benzonitrile.

In one embodiment, the compound is9-((1r,4r)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is2-(9-((1s,4s)-4-(aminomethyl)cyclohexyl)-8-(3-chlorophenylamino)-9H-purin-2-ylamino)-2-methylpropan-1-ol.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclobutyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-(4-aminocyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound isN2-tert-butyl-N8-(3-chloro-2-fluorophenyl)-9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine.

Also provided herein are compounds selected from Table 2.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-cyclopropyl-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(cyclopropylmethyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2,2-trifluoroethyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is((1s,4s)-4-(8-(3-chlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2,N2-dimethyl-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2,2-trifluoroethyl)-9H-purine-2,8-diamine.

In one embodiment, the compound is4-(9-((1s,4s)-4-(aminomethyl)cyclohexyl)-8-(3-chlorophenylamino)-9H-purin-2-ylamino)-1-methylcyclohexanol.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2,N2-dimethyl-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-(pyrrolidin-1-yl)-9H-purin-8-amine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

In one embodiment, the compound is9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine.

Each of the compounds in Table 1 and Table 2 was tested in one or moreof the in vitro parasite growth assays and was found to have activitytherein.

Methods for Making Compounds

The Aminopurine Compounds of Formula I can be made using conventionalorganic syntheses and commercially available starting materials. By wayof example and not limitation, Aminopurine Compounds of formula (I) canbe prepared as described in U.S. Pat. No. 7,723,340, and U.S. Pat. No.8,158,635, or as outlined in Scheme 1, shown below, as well as in theexamples set forth herein. It should be noted that one skilled in theart would know how to modify the procedures set forth in theillustrative schemes and examples to arrive at the desired products.

As shown in Scheme 1, compounds of formula (I), wherein R¹, R² and R³are as defined herein, can be prepared starting from an appropriatelyderivatized nitropyrimidine, wherein Hal¹ is Cl, and Hal² is Cl.Treatment of the dihalogenated nitropyrimidine with the appropriateR²NH₂ amine derivative, in the presence of a base, such as, for example,DIEA, TEA, sodium carbonate, sodium bicarbonate or pyridine, in asolvent, such as for example, DCM, DMF, dioxane or THF, at reducedtemperature (for example, −78° C.), provided incorporation of the R²sidechain. Treatment of this product with R¹NH₂, in the presence of abase, such as, for example, DIEA, TEA, sodium carbonate, sodiumbicarbonate or pyridine, in a solvent, such as for example, DCM, DMF,dioxane or THF, at temperatures ranging from 0-60° C., resulted inincorporation of the R¹ sidechain. Reduction of the nitro moiety, using,a reducing agent in a solvent (for example, hydrogen in the presence ofa catalyst such as Pd/C, in a solvent, such as MeOH or ethyl acetate, oriron in the presence of ammonium chloride in a solvent, such as forexample, EtOH, MeOH or water) provided the aminopyrimidine derivative.The aminopyrimidine derivative was treated with R³NCS, in a solvent,such as THF, DMF, NMP, dioxane, or EtOH, to obtain the (optionallyisolated) thiourea derivative, which was cyclized, using for example,EDC or DIC, in a solvent, for example, THF, dioxane, NMP or DMF,optionally at elevated temperature (for example, 40-80° C.), to providecompounds of formula (I).

In one aspect, provided herein are methods for preparing an AminopurineCompound of formula (I):

the methods comprising contacting a compound of formula (Ia)

with EDC or DIC, in a solvent, under conditions suitable to provide anAminopurine Compound of formula (I), wherein:

R¹ is CR^(1a)R^(1b)R^(1c), wherein each of R^(1a), R^(1b) and R^(1c) isindependently (C₁₋₄)alkyl, or (C₁₋₄)alkyl(OR); or R^(1a) and R^(1b) andthe carbon to which they are attached form a 3-6 membered cycloalkyl or3-6 membered heterocyclyl, and R^(1c) is (C₁₋₄)alkyl;

R² is cycloalkyl or aryl, substituted with at least one NR₂, OR, CN,NRC(O)R, CH₂OR, CH₂NR₂, CH₂NRCOR, CH₂NRCOOR′, or heterocyclylalkyl;

R³ is phenyl or pyridyl, optionally substituted with at least onehalogen, CN, (C₁₋₂)alkyl, or O(C₁₋₂)alkyl, wherein the alkyl isoptionally fluorinated;

R is H or (C₁₋₄) alkyl; and

R′ is (C₁₋₄)alkyl;

provided the Aminopurine Compound of formula (I) is not

-   4-(2-(tert-butylamino)-8-((2,6-difluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol;-   4-(2-(tert-butylamino)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol;    or-   4-(2-(tert-butylamino)-8-((2,4-difluorophenyl)amino)-9H-purin-9-yl)cyclohexan-1-ol.

In one embodiment, the solvent is THF, dioxane, NMP or DMF. In someembodiments, the contacting is optionally performed at elevatedtemperature, for example, from about 40° C. to about 80° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ia):

the methods comprising contacting a compound of formula (Ib)

with R³NCS, in a solvent, under conditions suitable to provide acompound of formula (Ia).

In one embodiment, the solvent is THF, DMF, NMP, dioxane, or EtOH.

In some embodiments, the methods further comprise preparing a compoundof formula (Ib):

the methods comprising reducing a compound of formula (Ic)

with a reducing agent, in a solvent, under conditions suitable toprovide a compound of formula (Ib).

In one embodiment, the reducing agent is H₂ in the presence of acatalyst. In some such embodiments, the catalyst Pd/C. In some suchembodiments, the solvent is MeOH or ethyl acetate. In other embodiments,the reducing agent is iron in the presence of ammonium chloride. In somesuch embodiments, the solvent is EtOH, MeOH or water.

In some embodiments, the methods further comprise preparing a compoundof formula (Ic):

the methods comprising contacting a compound of formula (Id)

with R¹NH₂, in the presence of a base, in a solvent under conditionssuitable to provide a compound of formula (Ic), wherein Hal¹ is Cl.

In some embodiments, the base is DIEA, TEA, sodium carbonate, sodiumbicarbonate, or pyridine. In other embodiments, the solvent is DCM, DMF,dioxane or THF. In some embodiments, the contacting is performed atelevated temperature, for example, from about 0° C. to about 60° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Id):

the methods comprising contacting a compound of formula (Ie)

-   -   with R²NH₂, in the presence of a base, in a solvent, under        conditions suitable to provide a compound of formula (Id),        wherein Hal² is Cl.

In some embodiments, the base is DIEA, TEA, sodium carbonate, sodiumbicarbonate, or pyridine. In other embodiments, the solvent is DCM, DMF,dioxane or THF. In some embodiments, the contacting is performed atreduced temperature, for example, about −78° C.

Methods of Use

The Aminopurine Compounds, including compounds of formula (I), Table 1and Table 2, have utility as pharmaceuticals to treat, prevent orimprove conditions in animals or humans. The Aminopurine Compoundsprovided herein are intended for use in the treatment or prevention ofall diseases, disorders or conditions disclosed herein. Accordingly, theAminopurine Compounds provided herein are for use as a medicament.Accordingly, provided herein are the Aminopurine Compounds for use inmethods of treatment or prevention of trypanosomosis, trypanosomiasisand/or leishmaniasis. The methods provided herein comprise theadministration of an effective amount of at least one AminopurineCompound(s) to a subject in need thereof.

The Aminopurine Compounds provided herein can be administered incombination with a second active agent. Accordingly, the AminopurineCompounds provided herein and the second active agent provided hereincan be used in the treatment or prevention of all diseases, disorders orconditions provided herein.

In one aspect, provided herein are methods of treating or preventingtrypanosomosis, trypanosomiasis and/or leishmaniasis, comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein. In one aspect, providedherein are Aminopurine Compounds for use in methods of treating orpreventing trypanosomosis, trypanosomiasis and/or leishmaniasis,comprising administering to a subject in need thereof an effectiveamount of an Aminopurine Compound, as described herein. In anotheraspect provided herein are compounds for treating or preventingtrypanosomosis, trypanosomiasis and/or leishmaniasis, comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein.

In one embodiment, the trypanosomosis or trypanosomiasis is caused byTrypanosoma avium, T. boissoni, T. brucei, T. b. gambiense, T. b.rhodesiense, T. b. evansi, T. carassii, T. cruzi, T. congolense, T.equinum, T. equiperdum, T. evansi, T. godfreyi, T. hosei, T. levisi, T.melophagium, T. parroti, T. percae, T. rangeli, T. rotatorium, T.rugosae, T. sergenti, T. simiae, T. sinipercae, T. suis, T. theileri, T.triglae and T. vivax. In some embodiments, the trypanosomosis ortrypanosomiasis is caused by T. congolense, T. vivax or T. evansi. Insome embodiments, the subject is an animal, and the trypanosomosis ortrypanosomiasis is caused by T. congolense, T. vivax, T. brucei brucei,T. evansi or T. simiae. In some embodiments, the subject is a human, andthe trypanosomosis or trypanosomiasis is caused by T. bruceirhodesiense, T. brucei gambiense or T. cruzi.

In some embodiments, the leishmaniasis is caused by L. donovani, L.infantum, L. chagasi; L. mexicana, L. amazonensis, L. venezuelensis, L.tropica, L. major, L. aethiopica, L. (V.) braziliensis, L. (V.)guyanensis, L. (V.) panamensis, or L. (V.) peruviana. In one embodiment,the subject is a human and the leishmaniasis is caused by L. major, L.tropica, L. aethiopica, L. mexicana, L. donovani or L. infantum.

In some embodiments, the trypanosomosis is Animal trypanosomosis orAfrican animal trypanosomosis (AAT). In other embodiments, thetrypanosomiasis is Human African trypanosomiasis (HAT, also known assleeping sickness). In other embodiments, the trypanosomiasis isAmerican trypanosomiasis or Chagas disease.

Also provided herein are methods of treating or preventing Animaltrypanosomosis or African animal trypanosomosis (AAT), comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein. Also provided herein areAminopurine Compounds, as described herein, for use in methods oftreating or preventing Animal trypanosomosis or African animaltrypanosomosis (AAT), comprising administering to a subject in needthereof an effective amount of an Aminopurine Compound, as describedherein. In some such embodiments, the subject is selected from cattle,sheep, goats, pigs, and dogs, and the Animal trypanosomosis or Africananimal trypanosomosis is caused by T. vivax, T. congolense, T. brucei,or T. evansi. In other such embodiments, the subject is selected fromhorses and donkeys, and the Animal trypanosomosis or African animaltrypanosomosis is caused by T. equiperdum. In yet other embodiments, thesubject is selected from dogs, horses and cats, and the Animaltrypanosomosis or African animal trypanosomosis is caused by T. bruceibrucei. In still other embodiments, the subject is selected from horses,camels, water buffalo and cattle, and the Animal trypanosomosis orAfrican animal trypanosomosis is caused by T. brucei evansi.

In some embodiments, the trypanosomosis is Nagana and is caused by T.congolense or T. vivax. In other embodiments, the trypanosomosis isSurra and is caused by T. evansi. In yet other embodiments, thetrypanosomosis is Dourine and is caused by T. equiperdum.

Also provided herein are methods of treating or preventing Animaltrypanosomosis or African animal trypanosomosis (AAT), comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein, in combination with a secondactive agent. Also provided herein are Aminopurine Compounds, asdescribed herein, for use in methods of treating or preventing Animaltrypanosomosis or African animal trypanosomosis (AAT), comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein, in combination with a secondactive agent. In one embodiment, the second active agent is at least oneof diminazene in various salt forms, including diminazene di-aceturate(i.e. Berenil®, Veriben®, Trypan®, Trypadim®, Trypazene®, Trypamyl®,Diamyl® Diminazen®); quinapyramine sulphate (Triquin®, Anthrycide®,Trypacide®, Trybexin®, Noroquin®); melarsomine (Cymelarsan®);isometamidium (Trypamidium®, Samorin®, Veridium®, Securidium); homidiumchloride or bromide (Novidium®, Ethidium®). In another embodiment, themethods additionally may comprise administering at least one of anantibiotic, an anti-parasitic, an anti-inflammatory and/or a vitamin.

Also provided herein are methods of treating or preventing Human Africantrypanosomiasis (HAT), comprising administering to a subject in needthereof an effective amount of an Aminopurine Compound, as describedherein. Also provided herein are Aminopurine Compounds, as describedherein, for use in methods of treating or preventing Human Africantrypanosomiasis (HAT), comprising administering to a subject in needthereof an effective amount of an Aminopurine Compound, as describedherein. In some such embodiments, the Human African trypanosomiasis iscaused by T. brucei gambiense, T. brucei brucei, or T. bruceirhodesiense.

Also provided herein are methods of treating or preventing Human Africantrypanosomiasis (HAT), comprising administering to a subject in needthereof an effective amount of an Aminopurine Compound, as describedherein, in combination with a second active agent. Also provided hereinare Aminopurine Compounds, as described herein, for use in methods oftreating or preventing Human African trypanosomiasis (HAT), comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein, in combination with a secondactive agent. In some embodiments, the second active agent is selectedfrom pentamidine, suramin, melarsoprol (arsenic-derived), eflornithineand nifurtimox.

Also provided herein are methods of treating or preventing Americantrypanosomiasis or Chagas disease, comprising administering to a subjectin need thereof an effective amount of an Aminopurine Compound, asdescribed herein. Also provided herein are Aminopurine Compounds, asdescribed herein, for use in methods of treating or preventing Americantrypanosomiasis or Chagas disease, comprising administering to a subjectin need thereof an effective amount of an Aminopurine Compound, asdescribed herein. In some such embodiments, the American trypanosomiasisor Chagas disease is caused by T. cruzi.

Also provided herein are methods of treating or preventing the Americantrypanosomiasis or Chagas disease, comprising administering to a subjectin need thereof an effective amount of an Aminopurine Compound, asdescribed herein, in combination with a second active agent. Alsoprovided herein are Aminopurine Compounds, as described herein, for usein methods of treating or preventing the American trypanosomiasis orChagas disease, comprising administering to a subject in need thereof aneffective amount of an Aminopurine Compound, as described herein, incombination with a second active agent. In some embodiments, the secondactive agent is selected from benznidazole and nifurtimox.

Also provided herein are methods of treating or preventingleishmaniasis, comprising administering to a subject in need thereof aneffective amount of an Aminopurine Compound, as described herein. Alsoprovided herein are Aminopurine Compounds, as described herein, for usein methods of treating or preventing leishmaniasis, comprisingadministering to a subject in need thereof an effective amount of anAminopurine Compound, as described herein. In some such embodiments, theleishmaniasis is caused by Leishmania. In some such embodiments, thesubject is a mammal, for example, a human or a rodent. In someembodiments, the leishmaniasis is visceral leishmaniasis (also known askala-azar) and is caused by L. donovani or L. infantum. In anotherembodiment the Leishmaniasis is post-kala-azar dermal leishmaniasis(PKDL). In yet other embodiments, the Leishmaniasis is cutaneous and iscaused by L. major, L. tropica, L. aethiopica or L. Mexicana. In stillother embodiments, the leishmaniasis is mucocutaneous leishmaniasis.

Also provided herein are methods of treating or preventingLeishmaniasis, comprising administering to a subject in need thereof aneffective amount of an Aminopurine Compound, as described herein, incombination with a second active agent. Also provided herein areAminopurine Compounds, as described herein, for use in methods oftreating or preventing Leishmaniasis, comprising administering to asubject in need thereof an effective amount of an Aminopurine Compound,as described herein, in combination with a second active agent. In someembodiments, the second active agent is selected from pentavalentantimonials (meglumine antimoniate and sodium stibogluconate;Pentostam®), Amphotericin B deoxycholate (also AmBisome®), pentamidine,paromomycin sulfate (aminosidine), miltefosine (hexadecylphosphocholine)and ketoconazole.

Pharmaceutical Compositions and Routes of Administration

Provided herein are pharmaceutical compositions comprising an effectiveamount of an Aminopurine compound, as described herein, and apharmaceutically acceptable carrier, excipient or vehicle. TheAminopurine Compounds can be administered to a subject enterally (forexample, orally, rectally), topically, or parenterally (for example,intravenously, intramuscularly, subcutaneously), in the conventionalform of preparations, such as capsules, microcapsules, tablets,granules, powder, troches, pills, suppositories, injections,suspensions, syrups, patches, creams, lotions, ointments, gels, sprays,solutions and emulsions. Suitable formulations can be prepared bymethods commonly employed using conventional, organic or inorganicadditives, such as an excipient (e.g., sucrose, starch, mannitol,sorbitol, lactose, glucose, cellulose, talc, calcium phosphate orcalcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate,calcium phosphate or calcium citrate), a lubricant (e.g., magnesiumstearate, light anhydrous silicic acid, talc or sodium lauryl sulfate),a flavoring agent (e.g., citric acid, menthol, glycine or orangepowder), a preservative (e.g, sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrrolidone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), a cosolvent(e.g. propylene glocyl/glycofurol), a buffer, a copolymer (e.g.poly(lactic-co-glycolic acid, i.e PLGA), and base wax (e.g., cocoabutter, white petrolatum or polyethylene glycol). The effective amountof the Aminopurine Compounds in the pharmaceutical composition may be ata level that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 20 mg/kg of a subject's bodyweight in unit dosage for both oral and parenteral administration.

The dose of an Aminopurine Compound to be administered to a subject israther widely variable and can be subject to the judgment of ahealth-care practitioner. In general, the Aminopurine Compounds can beadministered one to four times a day in a dose of about 0.005 mg/kg of asubject's body weight to about 20 mg/kg of a subject's body weight in asubject, but the above dosage may be properly varied depending on theage, body weight and medical condition of the subject and the type ofadministration. In one embodiment, the dose is about 0.01 mg/kg of asubject's body weight to about 5 mg/kg of a subject's body weight, about0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject'sbody weight, about 0.1 mg/kg of a subject's body weight to about 0.75mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's bodyweight to about 0.5 mg/kg of a subject's body weight. In one embodiment,the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kgof a subject's body weight. In one embodiment, the dose is about 0.05mg/kg of a subject's body weight to about 1 mg/kg of a subject's bodyweight. In one embodiment, the dose is about 0.1 mg/kg of a subject'sbody weight to about 0.75 mg/kg of a subject's body weight. In oneembodiment, the dose is about 0.25 mg/kg of a subject's body weight toabout 0.5 mg/kg of a subject's body weight. In one embodiment, one doseis given per day. In any given case, the amount of the AminopurineCompound administered will depend on such factors as the solubility ofthe active component, the formulation used and the route ofadministration. In one embodiment, application of a topicalconcentration provides intracellular exposures or concentrations ofabout 0.01-10 μM.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day. In another embodiment, providedherein are methods for the treatment or prevention of a disease ordisorder comprising the administration of about 0.375 mg/day to about750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day toabout 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/dayto about 37 mg/day of an Aminopurine Compound to a subject in needthereof. In one embodiment, the methods for the treatment of a diseaseor disorder comprise the administration of about 0.375 mg/day to about750 mg/day of an Aminopurine Compound to a subject in need thereof. Inone embodiment, the methods for the treatment of a disease or disordercomprise the administration of about 0.75 mg/day to about 375 mg/day ofan Aminopurine Compound to a subject in need thereof. In one embodiment,the methods for the treatment of a disease or disorder comprise theadministration of about 3.75 mg/day to about 75 mg/day of an AminopurineCompound to a subject in need thereof. In one embodiment, the methodsfor the treatment of a disease or disorder comprise the administrationof about 7.5 mg/day to about 55 mg/day of an Aminopurine Compound to asubject in need thereof. In one embodiment, the methods for thetreatment of a disease or disorder comprise the administration of about18 mg/day to about 37 mg/day of an Aminopurine Compound to a subject inneed thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day toabout 800 mg/day or about 600 mg/day to about 800 mg/day of anAminopurine Compound to a subject in need thereof. In a particularembodiment, the methods disclosed herein comprise the administration of400 mg/day, 600 mg/day or 800 mg/day of an Aminopurine Compound to asubject in need thereof. The methods for the treatment of a disease ordisorder comprise the administration of about 1 mg/day to about 1200mg/day of an Aminopurine Compound to a subject in need thereof. Themethods for the treatment of a disease or disorder comprise theadministration of about 10 mg/day to about 1200 mg/day of an AminopurineCompound to a subject in need thereof. The methods for the treatment ofa disease or disorder comprise the administration of about 100 mg/day toabout 1200 mg/day of an Aminopurine Compound to a subject in needthereof. The methods for the treatment of a disease or disorder comprisethe administration of about 400 mg/day to about 1200 mg/day of anAminopurine Compound to a subject in need thereof. The methods for thetreatment of a disease or disorder comprise the administration of about600 mg/day to about 1200 mg/day of an Aminopurine Compound to a subjectin need thereof. The methods for the treatment of a disease or disordercomprise the administration of about 400 mg/day to about 800 mg/day ofan Aminopurine Compound to a subject in need thereof. The methods forthe treatment of a disease or disorder comprise the administration ofabout 600 mg/day to about 800 mg/day of an Aminopurine Compound to asubject in need thereof. In a particular embodiment, the methodsdisclosed herein comprise the administration of 400 mg/day of anAminopurine Compound to a subject in need thereof. In another particularembodiment, the methods disclosed herein comprise the administration of600 mg/day of an Aminopurine Compound to a subject in need thereof. Inanother particular embodiment, the methods disclosed herein comprise theadministration of 800 mg/day of an Aminopurine Compound to a subject inneed thereof. In another embodiment, provided herein are unit dosageformulations that comprise between about 1 mg and 500 mg, or betweenabout 500 mg and about 1000 mg of an Aminopurine Compound. In oneembodiment, provided herein is a unit dosage formulation that comprisebetween about 1 mg and 500 mg of an Aminopurine Compound. In oneembodiment, provided herein is a unit dosage formulation that comprisebetween about 500 mg and about 1000 mg of an Aminopurine Compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg,about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about500 mg and about 1000 mg of an Aminopurine Compound. In one embodiment,the unit dosage formulations comprises between about 1 mg and 200 mg ofan Aminopurine Compound. In one embodiment, the unit dosage formulationscomprises between about 35 mg and about 1400 mg of an AminopurineCompound. In one embodiment, the unit dosage formulations comprisesbetween about 125 mg and about 1000 mg of an Aminopurine Compound. Inone embodiment, the unit dosage formulations comprises between about 250mg and about 1000 mg of an Aminopurine Compound. In one embodiment, theunit dosage formulations comprises between about 500 mg and about 1000mg of an Aminopurine Compound.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 100 mg or 400 mg of an Aminopurine Compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg,100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg,560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of an Aminopurine Compound.In one embodiment the unit dosage formulations comprise 1 mg of anAminopurine Compound. In one embodiment the unit dosage formulationscomprise 5 mg of an Aminopurine Compound. In one embodiment the unitdosage formulations comprise 10 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 15 mg of an AminopurineCompound. In one embodiment the unit dosage formulations comprise 20 mgof an Aminopurine Compound. In one embodiment the unit dosageformulations comprise 25 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 30 mg of an AminopurineCompound. In one embodiment the unit dosage formulations comprise 35 mgof an Aminopurine Compound. In one embodiment the unit dosageformulations comprise 40 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 50 mg of an AminopurineCompound. In one embodiment the unit dosage formulations comprise 70 mgof an Aminopurine Compound. In one embodiment the unit dosageformulations comprise 100 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 125 mg of anAminopurine Compound. In one embodiment the unit dosage formulationscomprise 140 mg of an Aminopurine Compound. In one embodiment the unitdosage formulations comprise 175 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 200 mg of anAminopurine Compound. In one embodiment the unit dosage formulationscomprise 250 mg of an Aminopurine Compound. In one embodiment the unitdosage formulations comprise 280 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 350 mg of anAminopurine Compound. In one embodiment the unit dosage formulationscomprise 500 mg of an Aminopurine Compound. In one embodiment the unitdosage formulations comprise 560 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 700 mg of anAminopurine Compound. In one embodiment the unit dosage formulationscomprise 750 mg of an Aminopurine Compound. In one embodiment the unitdosage formulations comprise 1000 mg of an Aminopurine Compound. In oneembodiment the unit dosage formulations comprise 1400 mg of anAminopurine Compound.

An Aminopurine Compound can be administered once, twice, three, four ormore times daily. In a particular embodiment, doses of 600 mg or lessare administered as a once daily dose and doses of more than 600 mg areadministered twice daily in an amount equal to one half of the totaldaily dose.

An Aminopurine Compound can be administered orally for reasons ofconvenience. In one embodiment, when administered orally, an AminopurineCompound is administered with a meal and water. In another embodiment,the Aminopurine Compound is dispersed in water or juice (e.g., applejuice or orange juice) and administered orally as a suspension.

The Aminopurine Compound can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin. The mode of administrationis left to the discretion of the health-care practitioner, and candepend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing anAminopurine Compound without an additional carrier, excipient orvehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of an Aminopurine Compound and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories,suspensions, gels, intra-ruminal devices (e.g. for prolonged prophylaxisor controlled release), implants, topical pour-ons, transdermal deliverygels, spot-ons, implants (including devices, gels, liquids (e.g. PLGA),and the like. Compositions can be formulated to contain a daily dose, ora convenient fraction of a daily dose, in a dosage unit, which may be asingle tablet or capsule or convenient volume of a liquid. In oneembodiment, the solutions are prepared from water-soluble salts, such asthe hydrochloride salt. In general, all of the compositions are preparedaccording to known methods in pharmaceutical chemistry. Capsules can beprepared by mixing an Aminopurine Compound with a suitable carrier ordiluent and filling the proper amount of the mixture in capsules. Theusual carriers and diluents include, but are not limited to, inertpowdered substances such as starch of many different kinds, powderedcellulose, especially crystalline and microcrystalline cellulose, sugarssuch as fructose, mannitol and sucrose, grain flours and similar ediblepowders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the dye. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer an Aminopurine Compound as asuppository, typical bases can be used. Cocoa butter is a traditionalsuppository base, which can be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the Aminopurine Compound can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of theAminopurine Compound can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the Aminopurine Compound in oily or emulsifiedvehicles, or adding amounts of PLGA, that allow it to disperse slowly inthe serum.

EXAMPLES

The following Examples are presented by way of illustration, notlimitation. Compounds are named using the automatic name generating toolprovided in Chemdraw Ultra 9.0 (Cambridgesoft), which generatessystematic names for chemical structures, with support for theCahn-Ingold-Prelog rules for stereochemistry. One skilled in the art canmodify the procedures set forth in the illustrative examples to arriveat the desired products.

Abbreviations Used

Boc t-Butyloxycarbonyl Cbz Carboxybenzyl CDI Carbonyldiimidazole DASTDiethylaminosulfur trifluoride DBU 1 8-Diazabicyclo 5.4.0 undec-7-eneDCM Dichloromethane DEA Diethylamine DIC Diisopropylcarbodiimide DIPEADiisopropylethylamine DMA N,N-Dimethylacetamide DME 1,2-DimethoxyethaneDMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DPPA Diphenylphosphorylazide EDCI Ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochlorideESI Electrospray ionization EtOH Ethanol HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HBTUO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphateHCl Hydrochloric acid HMPA Hexamethylphosphoramide HOBt1-Hydroxybenzotriazole HPLC High performance liquid chromatography HTRFHomogeneous time resolved fluorescence KOAc Potassium acetate LAHLithium aluminum hydride LCMS Liquid chromatography mass spectrometrymCPBA Meta-chloroperoxybenzoic acid MeOH Methanol MS Mass spectrometryMTBE tert-Butyl Methyl ether NaOH Sodium hydroxide NMMN-Methylmorpholine NMP N-methylpyrrolidone NMR Nuclear magneticresonance POCl₃ Phosphorus trichloride pTSA p-Toluenesulfonic acid SEM2-Trimethylsilylethoxymethoxy SFC Supercritical fluid chromatographyTBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroboratet-BuOH Tert-butanol TEA Triethylamine TFA Trifluoracetic acid THFTetrahydrofuran THP Tetrahydropyran TLC Thin layer chromatography TMSTrimethylsilane UPLC Ultra Performance Liquid Chromatography

Compound Synthesis Example 1:N8-(3-Chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(piperidin-1-ylmethyl)cyclohexyl)-9H-purine-2,8-diamine

tert-Butyl (1S, 4S)-4-(piperidine-1-carbonyl)cyclohexyl)carbamate

To a stirred solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1.5 g,6.0 mmol) in DMF (20 mL) was added DIPEA (2 ml, 12.5 mmol), piperidine(0.63 g, 7.5 mmol), EDCI (2.35 g, 12.5 mmol) and HOBT (1.88 g, 12.5mmol) at ambient temperature. The reaction mixture was stirred for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and triturated with petroleum ether to afford tert-butyl ((1S,4S)-4-(piperidine-1-carbonyl)cyclohexyl)carbamate (1.9 g) as anoff-white solid. MS (ESI) m/z 311 [M+1]⁺.

((1S, 4S)-4-Aminocyclohexyl)(piperidin-1-yl)methanone

To a stirred solution of tert-butyl ((1S,4S)-4-(piperidine-1-carbonyl)cyclohexyl)carbamate (1.9 g, 6.5 mmol) inDCM (20 mL) was added HCl in dioxane (2 mL) at 0° C. The reactionmixture was stirred at ambient temperature for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated to afford ((1S,4S)-4-aminocyclohexyl)(piperidin-1-yl)methanone. MS (ESI) m/z 211[M+1]⁺.

((1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (1 g, 5.5 mmol)and DIPEA (6.5 mL, 57 mmol) in IPA (20 mL) was added ((1S,4S)-4-aminocyclohexyl)(piperidin-1-yl)methanone (1.2 g, 6 mmol)portionwise at 0° C. under nitrogen. The reaction mixture was slowlywarmed to ambient temperature and stirred for 5 h. Completion of thereaction was confirmed by TLC. The product was isolated to afford ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone(0.5 g, 30%) as yellow solid. MS (ESI) m/z 369, 370 [M, M+1]⁺.

((1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone

To a stirred solution of ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone(0.5 g 1.5 mmol) in DMF (10 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.25 g, 2 mmol) and sodiumbicarbonate (0.43 g, 4 mmol) at ambient temperature. The reactionmixture was stirred at 60° C. for 2 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated and triturated withpetroleum ether to afford ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone.(0.4 g, 66%) as yellow solid. MS (ESI) m/z 447 [M+1]⁺.

((1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone

To a stirred solution of ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone(0.4 g, 1 mmol) in ethanol:water (20 mL, 3:1) was added iron powder (0.5g, 10 mmol) and ammonium chloride (0.05 g, 1 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 5 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone(0.35 g, 93%) as a brown solid. MS (ESI) m/z 417.4 [M+1]⁺.

(4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)(piperidin-1-yl)methanone

To a stirred solution of ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(piperidin-1-yl)methanone(0.2 g, 0.5 mmol) and 1-chloro-3-isothiocyanatobenzene (0.1 g, 0.6 mmol)in THF (10 mL) was added EDCI (0.19 g, 1 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)(piperidin-1-yl)methanone(0.1 g, 38%) as an off-white solid. MS (ESI) m/z 553, 554 [M, M+1]⁺.

N8-(3-Chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(4-(piperidin-1-ylmethyl)cyclohexyl)-9H-purine-2,8-diamine

To a stirred solution of(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)(piperidin-1-yl)methanone(0.1 g, 0.2 mmol) in THF (15 mL) was added dropwise lithium aluminiumhydride in THF (1.6 M, 0.5 mL) at 0° C. for 2 h. Completion of thereaction was confirmed by TLC. The product was isolated and purified viastandard methods to affordN8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-(4-(piperidin-1-ylmethyl)cyclohexyl)-9H-purine-2,8-diamine.(8 mg, 10%). MS (ESI) m/z 538, 539 [M, M+1]+. ¹H NMR (400 MHz, CD₃OD): δ8.21 (s, 1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.35-7.39 (m, 1H), 7.14 (d,J=7.6 Hz, 1H), 4.49-4.52 (m, 1H), 3.78-3.83 (m, 5H), 3.64-3.67 (m, 3H),3.02-3.08 (m, 2H), 2.42-2.59 (m, 5H), 1.82-2.10 (m, 14H), 1.66 (s, 3H).

Example 2:N8-(3-Chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(morpholinemethyl)cyclohexyl)-9H-purine-2,8-diamine

tert-Butyl((1S, 4S)-4-(morpholine-4-carbonyl)cyclohexyl)carbamate

To a stirred solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (3 g, 12mmol) in DMF (30 mL) was added DIPEA (4.5 mL, 24 mmol), morpholine (1.28g, 14.76 mmol), EDCI (4.70 g, 24.6 mmol) and HOBT (3.76 g, 24.6 mmol) atambient temperature. The reaction mixture was stirred for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and triturated with petroleum ether to afford tert-butyl ((1S,4S)-4-(morpholine-4-carbonyl)cyclohexyl)carbamate (2.65 g, 75%) as anoff-white solid. MS (ESI) m/z 313 [M+1]⁺.

((1S, 4S)-4-Aminocyclohexyl)(morpholino)methanone

To a stirred solution of tert-butyl ((1S,4S)-4-(morpholine-4-carbonyl)cyclohexyl)carbamate (2.65 g, 8.5 mmol) inDCM (50 mL) was added HCl in dioxane (5 mL) at 0° C. The reactionmixture was stirred at ambient temperature for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated to afford ((1S,4S)-4-aminocyclohexyl)(morpholino)methanone.

((1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (1.2 g, 6 mmol)and DIPEA (2 mL, 12 mmol) in IPA (50 mL) was added ((1S,4S)-4-aminocyclohexyl)(morpholino)methanone (1.57 g, 7 mmol) portionwiseat 0° C. under nitrogen. The reaction mixture was slowly warmed toambient temperature and stirred for 5 h. Completion of the reaction wasconfirmed by TLC. The product was isolated to afford ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(1 g, 44%) as yellow solid.

((1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone

To a stirred solution of ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(0.5 g 1 mmol) in DMF (10 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.24 g, 1 mmol) and sodiumbicarbonate (0.29 g, 4 mmol) at ambient temperature. The reactionmixture was stirred at ambient temperature for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(0.45 g, 70%) as yellow solid. MS (ESI) m/z 449 [M+1]⁺.

((1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone

To a stirred solution of ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(0.45 g, 1 mmol) in ethanol:water (20 mL, 3:1) was added iron powder(0.56 g, 10 mmol) and ammonium chloride (0.05 g, 1 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 5 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(0.4 g) as a brown solid. MS (ESI) m/z 419.4 [M+1]⁺.

N8-(3-Chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(morpholinemethyl)cyclohexyl)-9H-purine-2,8-diamine

To a stirred solution of ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)(morpholino)methanone(0.4 g, 1.0 mmol) and 1-chloro-3-isothiocyanatobenzene (0.19 g, 1.1mmol) in THF (10 mL) was added EDCI (0.36 g, 2.00 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)(morpholino)methanone(0.2 g, 38%) as an off-white solid. MS (ESI) m/z 553, 554 [M, M+1]⁺.

N8-(3-Chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4(morpholinomethyl)cyclohexyl)-9H-purine-2, 8-diamine

To a stirred solution of(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)(morpholino)methanone(0.2 g, 0.36 mmol) in THF (15 mL) was added lithium aluminium hydride inTHF (1.6 M, 1 mL) dropwise at 0° C. The reaction mixture was stirred atambient temperature for 2 h. Completion of the reaction was confirmed byUPLC. The product was isolated and purified via standard methods toafford N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1S,4S)-4-(morpholinomethyl)cyclohexyl)-9H-purine-2,8-diamine (0.085 g,43%). MS (ESI) m/z 540, 541 [M, M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30(s, 1H), 7.70 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.30-7.34 (m, 1H), 7.04(d, J=7.6 Hz, 1H), 4.27-4.33 (m, 1H), 3.75-3.77 (m, 8H), 2.64-2.70 (m,2H), 2.54-2.58 (m, 6H), 2.33-2.42 (m, 2H), 2.07 (brs, 1H), 1.97-2.00 (m,2H), 1.76-1.82 (m, 6H), 1.66 (s, 3H).

Example 3: (1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

cis-(4-Carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester

cis-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid (1 equiv.) andTEA (1.1 equiv.) were dissolved in 0.3 M THF and the mixture was cooledto 0° C. Ethyl chloroformate (1.1 equiv.) was added drop-wise. Afterstirring at 0° C. for 30 min, NH₃ in THF was added. The mixture wasallowed to stir at −78° C. for 2 h. The mixture was diluted with water,and the solvent was evaporated until only water remained. The resultingprecipitate was collected by filtration and dried under vacuum to givecis (4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (45%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.10 (brs, 1H), 6.69 (brs,2H), 3.41 (brs, 1H), 2.10 (m, 1H), 1.72 (m, 2H), 1.53 (m, 2H), 1.42 (m,4H), 1.36 (s, 9H).

cis-4-Amino-cyclohexanecarboxylic acid amide hydrochloride

To a solution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butylester (1 equiv.) in 1/1 DCM/TFA. The mixture was stirred for 1 h. Thesolvents were evaporated under reduced pressure. To the resultingresidue was added 2M HCl/ether to give a white solid. The solvent wasevaporated. The resulting solid was treated with ether and filtered togive cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (100%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.08 (brs, 3H), 7.28(s, 1H), 6.78 (s, 1H), 3.06 (m, 1H), 2.22 (m, 1H), 1.86 (m, 2. H), 1.66(m, 4H), 1.48 (m, 2H).

(1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

(1S, 4S)-4-Aminocyclohexanecarboxamide hydrochloride (0.56 mol) and2,4-dichloro-5-nitropyrimidine (1 equiv.) were dissolved in DCM (0.16M). The mixture was cooled to −78° C. An addition funnel was chargedwith DIEA (3 equiv.) and DCM (1.0 M). The DIEA solution was addeddropwise via an addition funnel. After the addition was complete, thereaction was stirred for an additional 2 h at −78° C. The reaction wasmonitored by LCMS. Once the reaction was completed, the reaction mixturewas purified by standard methods to give (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(65%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.01 (s, 1H), 8.51 (d, J=7.6 Hz,1H), 7.23 (s, 1H), 6.75 (s, 1H), 4.26 (s, 1H), 2.24 (s, 1H), 1.60-1.83(m, 8H).

Example 4: -((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 17 mmol) in DMF (10 mL) was added sodium carbonate (5.3 g, 50mmol) portionwise followed by 2-methylbutane-2-amine (3 g, 20 mmol) atambient temperature. The reaction mixture was stirred for 16 h.Completion of the reaction was confirmed by LCMS. The product wasisolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (50 mL, 1:1) was added iron powder (8.4g, 80 mmol) followed by ammonium chloride (0.80 g, 8 mmol). The reactionmixture was heated to 85° C. for 16 h. Completion of the reaction wasconfirmed by LCMS. The resulting reaction mixture was filtered through abed of celite, washed with ethyl acetate and concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 95%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

1-Fluoro-2-isothiocyanato-4-(trifluoromethyl)benzene

To a stirred solution of 2-fluoro-5-(trifluoromethyl)aniline (2 g, 11mmol) in dichloromethane (25 mL) was added TEA (2.5 g, 22 mmol), thenthiophosgene (1.9 g, 16 mmol) was added dropwise at 0° C. The resultingreaction mixture was stirred at ambient temperature for 1 h. Completionof the reaction was confirmed by UPLC. The product was isolated viastandard purification methods to afford1-fluoro-2-isothiocyanato-4-(trifluoromethyl)benzene (0.75 g, 33%) as apale yellow liquid. MS (ESI) m/z 222 [M+1]⁺.

(1S,4S)-4-(8-((2-Fluoro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.7 g, 3 mmol) and1-fluoro-2-isothiocyanato-4-(trifluoromethyl)benzene (0.45 g, 2 mmol) atambient temperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-(8-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 43%) as an off-white solid. MS (ESI) m/z 536 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 1 mmol) in diethyl ether (10 mL) was added lithium aluminumhydride in THF (2.4 M; 5 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 2 h. Completion of the reaction was confirmedby UPLC. The product was isolated and purified by standard methods toafford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 10%). MS (ESI) m/z 522 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.14(brs, 1H), 7.93 (brs, 1H), 7.32-7.40 (m, 2H), 4.33-4.36 (m, 1H),3.75-3.81 (m, 4H), 2.94-2.98 (m, 2H), 2.61-2.68 (m, 2H), 2.33-2.36 (m,2H), 1.97-1.99 (m, 2H), 1.75-1.85 (m, 4H), 1.60 (s, 3H).

Example 5: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 16.7 mmol) in DMF (50 mL) was added4-methyltetrahydro-2H-pyran-4-amine (2.1 g, 18.3 mmol) and sodiumcarbonate (3.5 g, 33 mmol) at ambient temperature. The reaction mixturewas stirred for 12 h. Completion of the reaction was confirmed by UPLC.The product was isolated and triturated with petroleum ether to afford(1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.7 g, 43%) as an off-white solid. MS (ESI) m/z 379.2 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-(2-((4-methyl-tetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 2.64 mmol) in ethanol:water (30 mL, 3:1) was added iron powder(0.74 g, 13.2 mmol) and ammonium chloride (0.7 g, 13.2 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by LCMS. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 87%) as a brown solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(8-((3-Chloro-5-flurophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 1.15 mmol) and 1-chloro-3-fluoro-5-isothiocyanatobenzene (0.26g, 1.37 mmol) in ethanol was added DCC (0.71 g, 3.44 mmol) at ambienttemperature. The reaction mixture was stirred for 12 h. Completion ofthe reaction was confirmed by UPLC. The product was isolated andpurified via standard methods to afford (1S,4S)-4-(8-((3-chloro-5-flurophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 69%) as an off-white solid. MS (ESI) m/z 501.2, 502.2 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chloro-5-flurophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 0.77 mmol) in THF (20 mL) was added lithium aluminium hydride inTHF (2.4 M; 1.27 mL) dropwise at 0° C. and then heated at 50° C. for 8h. Completion of the reaction was confirmed by TLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.07 g, 17%). MS (ESI) m/z 488.2, 489.2 [M, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.27 (s, 1H), 7.51 (s, 1H), 7.43-7.46 (m, 1H), 6.82-6.85 (m,1H), 4.33-4.39 (m, 1H), 3.76-3.83 (m, 4H), 3.13-3.14 (m, 2H), 2.64-2.73(m, 2H), 2.41-2.44 (m, 2H), 1.76-2.01 (m, 9H and 3H), 1.61 (s, 3H).

Example 6: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium carbonate (5.3 g, 60mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred for 16h. Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (60 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(8-((2-Fluoro-3-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.6 g, 2 mmol) inTHF: DMF (1:1; 20 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and2-fluoro-1-isothiocyanato-3-(trifluoromethyl)benzene (0.5 g, 2 mmol) atambient temperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-(8-((2-fluoro-3-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 44%) as an off-white solid. MS (ESI) m/z 536 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((2-fluoro-3-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 5 mL) at 0° C. The reaction mixture was stirred at ambienttemperature for 3 h. Completion of the reaction was confirmed by UPLC.The product was purified by standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 10%). MS (ESI) m/z 522.2, 523.2 [M, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.56, 8.12 (s, 1H), 7.81-7.83 (m, 1H), 7.41-7.44 (m, 1H),7.31-7.35 (m, 1H), 4.35-4.41 (m, 1H), 3.76-3.78 (m, 4H), 2.95-2.97 (d,J=7.6 Hz, 2H), 2.62-2.72 (m, 2H), 2.34-2.37 (m, 2H), 1.97-2.00 (m, 2H),1.75-1.86 (m, 7H), 1.60 (s, 3H).

Example 7: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium carbonate (5.3 g, 60mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred for 16h. Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (60 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

2-Isothiocyanato-6-(trifluoromethyl)pyridine

To a stirred solution of 6-(trifluoromethyl)pyridin-2-amine (1 g, 6mmol) in dichloromethane (25 mL) was added saturated sodium bicarbonatesolution (25 mL). Thiophosgene (0.84 g, 7 mmol) was added dropwise at 0°C. The resulting reaction mixture was stirred at ambient temperature for1 h. Completion of the reaction was confirmed by UPLC. The product wasisolated to afford 2-isothiocyanato-6-(trifluoromethyl)pyridine (0.75 g,60%) as a yellow liquid. MS (ESI) m/z 205 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((6-(trifluoromethyl)pyridin-2-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF: DMF (1:1; 20 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and2-isothiocyanato-6-(trifluoromethyl)pyridine (0.4 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((6-(trifluoromethyl)pyridin-2-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.45 g, 50%) as an off-white solid. MS (ESI) m/z 536 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((6-(trifluoromethyl)pyridin-2-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 4 mL) at 0° C. The reaction mixture was stirred at ambienttemperature for 3 h. Completion of the reaction was confirmed by UPLC.The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine(0.08 g, 25%). MS (ESI) m/z 505 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.58,8.17-8.24 (s, 1H), 7.84-7.88 (m, 1H), 7.65 (brs, 1H), 7.31 (d, J=7.2 Hz,1H), 3.72-3.82 (m, 4H), 3.03 (d, J=7.2 Hz, 2H), 2.60-2.70 (m, 2H),2.35-2.39 (m, 2H), 1.91-2.01 (m, 3H), 1.74-1.84 (m, 6H), 1.60 (s, 3H).

Example 8: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium bicarbonate (5.3 g, 50mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred for 16h. Completion of the reaction was confirmed by UPLC. The product wasisolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (66 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1S, 4S)-4-(8-((3,5-Difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylamino propyl)carbodiimide (0.7 g, 3 mmol) and1,3-difluoro-5-isothiocyanatobenzene (0.35 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3,5-difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 42%) as an off-white solid. MS (ESI) m/z 485 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3,5-difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 1 mmol) in diethyl ether (5 mL) was added lithium aluminumhydride in THF (1.6 M; 4 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 2 h. Completion of the reaction was confirmedby UPLC. The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 15%). MS (ESI) m/z 472.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.25 (s, 1H), 7.27-7.30 (m, 2H), 6.55-6.66 (m, 1H), 4.32-4.39 (m, 1H),3.77-3.79 (m, 4H), 2.96-2.98 (d, J=7.2 Hz, 2H), 2.67-2.74 (m, 2H),2.34-2.38 (m, 2H), 1.98-2.01 (m, 2H), 1.75-1.87 (m, 5H), 1.71-1.75 (m,2H), 1.62 (s, 3H).

Example 9: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 16.7 mmol) in DMF (50 mL) was added4-methyltetrahydro-2H-pyran-4-amine (2.1 g, 18.3 mmol) and sodiumcarbonate (3.5 g, 33 mmol) at ambient temperature. The reaction mixturewas stirred for 12 h. Completion of the reaction was confirmed by UPLC.The product was isolated and triturated with petroleum ether to afford(1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.74 g, 43%) as an off-white solid. MS (ESI) m/z 379.2 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-(2-((4-methyl-tetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 2.64 mmol) in ethanol:water (30 mL, 3:1) was added iron powder(0.74 g, 13.2 mmol) and ammonium chloride (0.7 g, 13.2 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by LCMS. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (is4s)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 87%) as a brown solid. MS (ESI) m/z 349 [M+1]⁺.

(1S, 4S)-4-(8-((3,5-Dichlorophenyl)amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 1.2 mmol) and 1,3-dichloro-5-isothiocyanatobenzene (0.28 g, 1.4mmol) in ethanol was added DCC (0.71 g, 3.4 mmol) at ambienttemperature. The reaction mixture was stirred for 12 h. Completion ofthe reaction was confirmed by UPLC. The product was isolated andpurified via standard methods to afford (1S,4S)-4-(8-((3,5-dichlorophenyl)amino)-2-((4methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide.(0.4 g, 67%) as an off-white solid. MS (ESI) m/z 520.2 [M+2]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3,5-dichlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 0.77 mmol) in THF (20 mL) was added dropwise lithium aluminiumhydride in THF (2.4 M; 1.28 mL) at 0° C. and heated at 50° C. for 8 h.Completion of the reaction was confirmed by TLC. The product waspurified by standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.09 g, 23%). MS (ESI) m/z 504.46, 505.2 [M, M+2]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.27 (s, 1H), 7.65 (s, 2H), 7.07 (s, 1H), 4.34-4.40 (m, 1H),3.75-3.83 (m, 4H), 3.19-3.21 (m, 2H), 2.62-2.72 (m, 2H), 2.43-2.47 (m,2H), 2.00-2.10 (m, 1H), 2.0-2.02 (m, 2H), 1.87-1.92 (m, 1H), 1.75-1.85(m, 5H), 1.61 (s, 3H).

Example 10: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopropyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((1-Methylcyclopropyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3 mmol) in DMF (10 mL) was added sodium carbonate (1 g, 10 mmol)portionwise followed by 1-methylcyclopropan-1-amine hydrochloride (0.4g, 3 mmol) at ambient temperature. The reaction mixture was stirred for16 h. Completion of the reaction was confirmed by LCMS. The product wasisolated to afford (1S,4S)-4-((2-((1-methylcyclopropyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.9 g, 81%) as a yellow solid. MS (ESI) m/z 335 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((1-methylcyclopropyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((1-methylcyclopropyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.9 g, 2.7 mmol) in ethanol:water (20 mL, 1:1) was added iron powder(1.5 g, 26 mmol) followed by ammonium chloride (0.145 g, 2.7 mmol). Thereaction mixture was heated to 85° C. for 16 h. Completion of thereaction was confirmed by LCMS. The resulting reaction mixture wasfiltered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-((1-methylcyclopropyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 97%) as a violet solid. MS (ESI) m/z 305 [M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((1-methylcyclopropyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide

To stirred solution of (1S,4S)-4-((5-amino-2-((1-methylcyclopropyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.85 g, 2.8 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 g, 5.6 mmol) and1-chloro-3-isothiocyanatobenzene (0.6 g, 3.3 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification method to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclopropyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide(0.65 g, 58%) as a brown solid. MS (ESI) m/z 439, 440 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopropyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclopropyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 1 mmol) in diethyl ether (10 mL) was added lithium aluminumhydride in THF (2.4 M; 5 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 2 h. Completion of the reaction was confirmedby UPLC. The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopropyl)-9H-purine-2,8-diamine(0.1 g, 30%). MS (ESI) m/z 425.2, 426.2 [M, M+1]⁺. ¹HNMR (400 MHz,CD₃OD): δ 8.25 (s, 1H), 8.01 (s, 1H), 7.66-7.68 (d, J=8 Hz, 1H),7.31-7.35 (m, 1H), 6.98-7.00 (m, 1H), 4.34-4.40 (m, 1H), 2.89 (d, J=6.8Hz, 2H), 2.70-2.79 (m, 2H), 1.89-1.92 (m, 2H), 1.68-1.73 (m, 1H),1.58-1.64 (m, 4H), 1.42 (s, 3H) 0.64-0.70 (m, 4H).

Example 11: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3.33 mmol) in DMF (30 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.42 g, 3.67 mmol) and sodiumbicarbonate (0.56 g, 6.67 mmol) at ambient temperature. The reactionmixture was heated to 60° C. for 4 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated and triturated withpetroleum ether to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 63%) as an off-white solid. MS (ESI) m/z 379, 380 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.18 g, 2.11 mmol) in ethanol:water (30 mL, 10:1) was added iron powder(0.8 g, 21.13 mmol) and ammonium chloride (0.13 g, 2.53 mmol) at ambienttemperature. The reaction mixture was heated at 80° C. Completion of thereaction was confirmed by TLC. The resulting reaction mixture wasfiltered through bed of celite, washed with methanol and concentrated toafford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 82%) as a black solid. MS (ESI) m/z 349, 350 [M, M+1]⁺.

(1S,4S)-4-(8-((5-Chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 1.72 mmol) and 4-chloro-1-fluoro-2-isothiocyanatobenzene (0.35g, 1.89 mmol) in THF was added EDCI (0.66 g, 3.44 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3-chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 34%) as an off-white solid. MS (ESI) m/z 502, 503 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 0.59 mmol) in THF (10 mL) was added dropwise lithium aluminiumhydride in THF (1.6 M; 3 mL) at 0° C. The reaction was heated at 50° C.for 8 h. Completion of the reaction was confirmed by TLC. The productwas purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.015 g, 5%). MS (ESI) m/z 488, 489 [M, M+1]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.57 NH proton (brs, 0.5H), 8.19 (brs, 1H), 7.67 (brs, 1H), 7.13-7.22(m, 2H), 4.35-4.45 (m, 1H), 3.74-3.78 (m, 4H), 3.16-3.18 (m, 2H),2.64-2.68 (m, 2H), 2.42-2.46 (m, 2H), 1.97-2.06 (m, 3H), 1.74-1.89 (m,6H), 1.60 (s, 3H).

Example 12: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

2,2-Dimethyltetrahydro-2H-pyran-4-amine

To a stirred solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (2 g, 20mmol) in MeOH (40 mL) and H₂O (5 mL) was added ammonium formate (10.33g, 160 mmol) and pallidum on carbon (0.5 g). The reaction was stirredunder atmospheric hydrogen atmosphere for 5 h. The reaction mixture wasfiltered through bed of celite and washed with methanol. The resultingfiltrate was concentrated under reduced pressure to afford 2,2-dimethyltetrahydro-2H-pyran-4-amine (2.5 g, 85%) as a colourless gummymaterial.

(1S,4S)-4-((2-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5g, 2.2 mmol) in DMF (10 mL) was added2,2-dimethyltetrahydro-2H-pyran-4-amine (0.24 g, 1.8 mmol) and sodiumcarbonate (0.53 g, 5.0 mmol) at ambient temperature. The reactionmixture was stirred at ambient temperature for 16 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford (1S,4S)-4-((2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 61%) as an yellow solid. MS (ESI) m/z 393.2 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 1.01 mmol) in ethanol (24 mL) was added iron powder (0.57 g, 10mmol) and ammonium chloride (0.053 g, 1 mmol) under an inert atmosphereat ambient temperature. The reaction mixture was stirred at 80° C. for 6h. Completion of the reaction was confirmed by TLC. The resultingreaction mixture was filtered through bed of celite, washed with ethylacetate and concentrated to afford (1S,4S)-4-((5-amino-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g,) as a brown solid. MS (ESI) m/z 363.7 [M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 1.1 mmol) and 1-chloro-3-isothiocyanatobenzene (0.22 g, 1.32mmol) in THF (8 mL) was added EDCI (0.42 g, 2.2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 64%) as an off-white solid. MS (ESI) m/z 497, 498 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 0.70 mmol in THF (10 mL) was added lithium aluminium hydride inTHF (1.6 M; 3 mL) dropwise at 0° C. The reaction mixture was stirred atambient temperature for 18 h. Completion of the reaction was confirmedby TLC. The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.035 g, 10%) as an off-white solid. MS (ESI) m/z 484.2, 485.2 [M,M+1]+. ¹H NMR (400 MHz, CD₃OD): δ 8.57, 8.19 (s, 1H), 7.71 (s, 1H), 7.46(d, J=7.6 Hz, 1H), 7.30-7.34 (m, 1H), 7.04-7.06 (m, 1H), 4.32-4.38 (m,1H), 4.18-4.24 (m, 1H), 3.84-3.87 (m, 2H), 3.05-3.15 (m, 2H), 2.83-2.86(m, 1H), 2.69-2.72 (m, 1H), 2.07-2.11 (m, 1H), 1.87-2.00 (m, 8H),1.49-1.52 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H).

Example 13: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3.3 mmol) in DMF (30 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.42 g, 3.67 mmol) and sodiumbicarbonate (0.56 g, 6.7 mmol) at ambient temperature. The reactionmixture was heated to 60° C. for 4 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated and triturated withpetroleum ether to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 63%) as an off-white solid. MS (ESI) m/z 379, 380 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.18 g, 2.11 mmol) in ethanol (24 mL) and water (3 mL) was added ironpowder (0.8 g, 21.13 mmol) and ammonium chloride (0.13 g, 2.53 mmol) atambient temperature. The reaction mixture heated at 80° C. Completion ofthe reaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through bed of celite, washed with methanol and concentrated toafford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 82%) as a brown solid. MS (ESI) m/z 349, 350 [M, M+1]⁺.

(1S,4S)-4-(8-((3-Chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 1.7 mmol) and 1-chloro-2-fluoro-3-isothiocyanatobenzene (0.35 g,1.89 mmol) in THF (10 mL) was added EDCI (0.66 g, 3.44 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3-chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 34%) as an off-white solid. MS (ESI) m/z 502, 503 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chloro-2-fluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 0.59 mmol in THF (10 mL) was added lithium aluminium hydride inTHF (1.6 M; 3 mL) dropwise at 0° C. and heated at 50° C. for 8 h.Completion of the reaction was confirmed by TLC. The product wasisolated and purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(15 mg, 5%). MS (ESI) m/z 488.2, 489.2 [M, M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.22 (brs, 1H), 7.74 (brs, 1H), 7.18-7.23 (m, 1H), 7.14 (brs,1H), 4.45 (brs, 1H), 3.74-3.84 (m, 4H), 3.20-3.25 (m, 2H), 2.63-2.67 (m,2H), 2.46-2.50 (m, 2H), 2.00-2.17 (m, 1H), 1.90-1.97 (m, 6H), 1.83-1.89(m, 2H), 1.60 (s, 3H).

Example 14: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-(tert-Butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3.3 mmol) in DMF (30 mL) was added 2-methylpropan-2-amine (0.27 g,3.7 mmol) and sodium bicarbonate (0.56 g, 6.7 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and triturated with petroleum ether to afford (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 71%) as an off-white solid. MS (ESI) m/z 337, 338 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 2.38 mmol) in ethanol:water (27 mL, 10:1) was added iron powder(1.33 g, 23.78 mmol) and ammonium chloride (0.15 g, 2.85 mmol) atambient temperature. The reaction mixture heated at 80° C. Completion ofthe reaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through bed of celite, washed with methanol and concentrated toafford (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 83%) as a brown solid. MS (ESI) m/z 307, 308 [M, M+1]⁺.

(1S,4S)-4-(2-(tert-Butylamino)-8-((3,5-dichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 1.95 mmol) and 1,3-dichloro-5-isothiocyanatobenzene (0.43 g,2.15 mmol) in THF (10 mL) was added EDCI (0.75 g, 3.91 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford ((1S,4S)-4-(2-(tert-butylamino)-8-((3,5-dichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 32%) as an off-white solid. MS (ESI) m/z 477, 478 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine

To a stirred solution of ((1S,4S)-4-(2-(tert-butylamino)-8-((3,5-dichlorophenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 0.63 mmol) in THF (10 mL) was added lithium aluminium hydride inTHF (1.6 M; 3 mL) dropwise at 0° C. and heated at 50° C. for 8 h.Completion of the reaction was confirmed by TLC. The product wasisolated and purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine(0.015 g, 6%). MS (ESI) m/z 462.2, 463.2, 464.2, 465.2 [M, M+1, M+2,M+3]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.26 (s, 1H), 7.66 (s, 2H), 7.08 (s,1H), 4.38 (m, 1H), 2.72-2.76 (m, 2H), 2.16-2.20 (m, 1H), 1.91-1.20 (m,5H), 1.81-1.85 (m, 2H), 1.56 (s, 10H).

Example 15: ((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol

((1S, 4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of 2,4-dichloro-5-nitropyrimidine (0.4 g, 2 mmol)in THF (10 mL) was added DIPEA (0.2 g, 2 mmol) portionwise followed by((1S, 4S)-4-aminocyclohexyl)methanol (0.3 g, 2 mmol) at ambienttemperature. The reaction mixture was stirred for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated to afford ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.2 g,27%) as a yellow solid. MS (ESI) m/z 287 [M+1]⁺.

((1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.05g, 0.2 mmol) in DMF (10 mL) was added sodium carbonate (0.04 g, 0.4mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-aminehydrochloride (0.03 g, 0.2 mmol) at ambient temperature The reactionmixture was stirred for 4 h. Completion of the reaction was confirmed byUPLC. The product was isolated to afford ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.03 g, 50%) as a yellowsolid. MS (ESI) m/z 366 [M+1]⁺.

((1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol(0.1 g, 3 mmol) in ethanol:water (4 mL, 1:1) was added iron powder (0.2g, 2.7 mmol) portionwise followed by ammonium chloride (0.02 g, 0.3mmol) at ambient temperature. The reaction mixture was heated to 80° C.for 4 h. Completion of the reaction was confirmed by UPLC. The productwas isolated and purified via standard methods to afford ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol(0.08 g, 80%) as a yellow solid. MS (ESI) m/z 336 [M+1].

((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol

To a stirred solution of ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol(0.1 g, 3 mmol) in THF (100 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.07 g, 3 mmol) and1-isothiocyanato-3-chloro benzene (0.05 g 3 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford ((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol(0.06 g, 40%). MS (ESI) m/z 471 [M+1]+. ¹H NMR (400 MHz, CD₃OD): δ 8.20(s, 1H), 7.70 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.28-7.32 (m, 1H), 7.03(d, J=8.0 Hz, 1H), 4.32-4.38 (m, 1H),3.72-3.80 (m, 4H), 3.47-3.51 (m,2H), 2.64-2.71 (m, 2H), 2.35-2.38 (m, 2H), 1.93-2.04 (m, 4H), 1.74-1.80(m, 2H), 1.58-1.63 (m, 1H), 1.57 (s, 3H), 1.20-1.30 (m, 2H).

Example 16: 9-((1R,4R)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1R,4R)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (1.0 g, 5.15mmol) and DIPEA (2.75 mL, 15.45 mmol) in IPA (20 mL) was addedportionwise (1R, 4R)-4-aminocyclohexane-1-carboxamide (0.73 g, 5.15mmol) at 0° C. under N2. The reaction mixture was slowly warmed toambient temperature and stirred for 2 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated to afford (1r,4r)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.2 g) as pale yellow solid. MS (ESI) m/z 300, 301 [M, M+1]⁺.

(1R,4R)-4-((2-(tert-Butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1r,4r)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.2 g, 4 mmol), tert-butylamine (0.58 g, 8 mmol) and sodium bicarbonate(0.5 g, 6 mmol) in DMF (10 mL) was heated to 60° C. for 4 h. Completionof the reaction was confirmed by UPLC. The reaction mixture was dilutedwith water. The solid obtained was filtered, washed with water and driedunder vacuum to afford (1r,4r)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.0 g, 75%) as a pale yellow solid. MS (ESI) m/z 337 [M+1]⁺.

(1R,4R)-4-((5-Amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1r,4r)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.0 g, 3 mmol) in ethanol:water (20 mL, 3:1) was added iron powder(1.66 g, 30 mmol) and ammonium chloride (0.146 g, 3 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 2 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1r,4r)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.9 g) as a brown solid. MS (ESI) m/z307 [M+1]⁺.

(1R,4R)-4-(2-(tert-Butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1r,4r)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.42 g, 1.4 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.33g, 1.6 mmol) in THF was added EDCI (0.5 g, 2.7 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1r,4r)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.2 g, 31%) as a brown solid. MS (ESI) m/z476 [M+1]⁺.

9-((1R,4R)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1r,4r)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.18 g, 0.4 mmol) in THF (5 mL) was added 1.5 M solution of lithiumaluminium hydride (0.5 mL, 0.75 mmol) at 0° C. The reaction mixture wasstirred at 40° C. for 1 h. Completion of the reaction was confirmed byUPLC. The product was isolated and purified via standard methods toafford 9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine (0.05 g, 29%). MS (ESI) m/z 462 [M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.56 (s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.83 (d, J=8 Hz,1H), 7.50-7.54 (m, 1H), 7.32 (d, J=7.6 Hz, 1H), 4.36-4.42 (m, 1H),2.75-2.87 (m, 4H), 2.02-2.10 (m, 4H), 1.78-1.80 (m, 1H), 1.52 (s, 9H),1.28-1.36 (m, 2H).

Example 17:9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-pentyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((5-Nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in DMF (10 mL) was added sodium bicarbonate (0.17 g, 2mmol) portionwise followed by 2-methylbutane-2-amine (0.22 g, 2 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated to afford (1S,4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.6 g, 83%) as a yellow solid. MS (ESI) m/z351 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 2 mmol) in ethanol (10 mL) was added palladium on charcoal (0.06g, 10% W/M) portionwise under argon atmosphere. The reaction was stirredat ambient temperature under atmospheric hydrogen atmosphere. Completionof the reaction was confirmed by UPLC. The resulting reaction mixturewas filtered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 90%) as a yellow solid. MS (ESI) m/z 321 [M+1]⁺.

(1S,4S)-4-(2-(tert-Pentylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 1 mmol) in THF (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-isothiocyanato-3-(trifluoromethyl)benzene (0.3 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-(tert-pentylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 55%) as an off-white solid. MS (ESI) m/z 490 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-pentyl)-N8-(3-(trifluoromethyl)phenyl)9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-(tert-pentylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 2 mL) at 0° C. The reaction mixture was heated to 55° C. for 1h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(tert-pentyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.09 g, 30%). MS (ESI) m/z 476 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.50(s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.55(m, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.38-4.44 (m, 1H), 3.28 (d, J=7.6 Hz,2H), 2.66-2.76 (m, 2H), 2.17 (m, 1H), 1.83-2.05 (m, 8H), 1.50 (s, 6H),0.96 (m, 3H).

Example 18: Methyl (((1S, 4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate

Methyl (((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate

To a stirred solution of 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.1 g, 0.2 mmol) in methanol (5 mL) was added pyridine (0.02 g, 0.2mmol) portionwise followed by methylchloroformate (0.02 g, 0.2 mmol) at0° C. The reaction mixture was stirred for 30 minutes at 0° C.Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford methyl(((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate(0.02 g, 21%). MS (ESI) m/z 528 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.20(s, 1H), 7.71 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.29-7.33 (m, 1H), 7.04(d, J=8.0 Hz, 1H), 4.30-4.36 (m, 1H), 3.70-3.83 (m, 4H), 3.66 (s, 3H),3.40-3.50 (m, 2H), 2.70-2.80 (m, 2H), 2.35-2.38 (m, 2H), 1.91-1.95 (m,3H), 1.71-1.87 (m, 6H), 1.60 (s, 3H).

Example 19: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-(tert-Butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.0 g, 3.3 mmol) in DMF (10 mL) was added tert-butylamine (0.3 g, 4mmol) and sodium bicarbonate (0.84 g, 10 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 63%) as a yellow solid. MS (ESI) m/z 337 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 2 mmol) in ethanol (24 mL) was added palladium on carbon (0.1 g,W/W) under inert atmosphere at ambient temperature. The reaction mixturewas stirred under atmospheric hydrogen pressure at ambient temperature.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard methods to afford (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 90%) as a brown solid. MS (ESI) m/z 307 [M+1]⁺.

(1S,4S)-4-(2-(tert-Butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.5 g,2.0 mmol) in THF was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(0.75 g, 4 mmol) at ambient temperature. The reaction mixture was heatedto 50° C. for 4 h. Completion of the reaction was confirmed by TLC. Theproduct was isolated and purified via standard purification methods toafford (1S,4S)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide (0.45 g, 48%) as ayellow solid. MS (ESI) m/z 476 [M-H]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide (0.3 g, 0.13 mmol) inTHF (10 mL) was added dropwise lithium aluminium hydride in THF (1.6 M,5 mL) at 0° C. and heated at 45° C. for 8 h. Completion of the reactionwas confirmed by TLC. The product was purified via standard methods toafford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-2,8-diamine(0.06 g, 20%). MS (ESI) m/z 463 [M+1]+. ¹H NMR (400 MHz, CD₃OD): δ8.56,8.19 (brs, 1H), 7.88 (brs, 1H), 7.79-7.83 (m, 1H), 7.48-7.52 (m, 1H),7.30 (d, J=6.8 Hz, 1H), 4.31-4.38 (m, 1H), 3.15 (d, J=6.8 Hz, 2H),2.72-2.78 (m, 2H), 1.93-2.00 (m, 3H), 1.79-1.89 (m, 4H), 1.54 (s, 9H).

Example 20: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

N-Methyltetrahydro-2H-pyran-4-amine

To a stirred solution of tetrahydro-4H-pyran-4-one (1 g, 10 mmol) in THF(10 mL) was added methylamine (0.62 g, 20 mmol, 2 M solution in THF)dropwise at ambient temperature followed by acetic acid (0.5 mL). Thereaction mixture was stirred for 1 h. Sodium cyanoborohydride (0.7 g, 12mmol) was added to the reaction mixture at 0° C. and continued stirringat ambient temperature for 16 h. Completion of the reaction wasconfirmed by TLC. The product was isolated to affordN-methyltetrahydro-2H-pyran-4-amine (1 g) as a yellow color liquid. GCMS(ESI) m/z 115 [M]⁺.

(1S,4S)-4-((2-(Methyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (5 g, 7 mmol) in DMF (10 mL) was addedN-methyl tetra-hydro-2H-pyran-4-amine (1 g, 8 mmol) and sodium carbonate(2 g, 20 mmol) under nitrogen atmosphere. The reaction was stirred atambient temperature for 16 h. Completion of the reaction was confirmedby UPLC. Product was isolated via standard purification methods toafford (1S,4S)-4-((2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 22%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 1 mmol) in ethanol (10 mL) was added palladium on carbon (0.04g, W/W) under inert atmosphere at ambient temperature. The reactionmixture was stirred under atmospheric hydrogen pressure at ambienttemperature. Completion of the reaction was confirmed by UPLC. Theproduct was isolated via standard methods to afford (1S,4S)-4-((5-amino-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.35 g, 94%) as a brown solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((5-amino-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.35 g, 1 mmol) in THF (10 mL) was added1-chloro-3-isothiocyanatobenzene (0.2 g, 1 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.4 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.23 g, 47%) as pale yellow solid. MS (ESI) m/z 484, 485 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.23 g, 0.5 mmol) in THF (5 mL) was added lithium aluminum hydride inTHF (1.6 M; 4 mL) at 0° C. The reaction mixture was heated to 45° C. for1 h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 22%). MS (ESI) m/z 470, 471 [M, M+1]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.57 (s, 1H), 8.27 (s, 1H), 7.65 (s, 1H), 7.42 (d, J=8 Hz, 1H),7.27-7.31 (t, J=8 Hz, 1H), 7.01-7.03 (dd, J=1.6 Hz & 8 Hz, 1H),4.81-4.87(m, 1H), 4.31-4.37 (m, 1H), 4.06-4.10 (m, 2H), 3.55-3.61 (m, 2H),3.15-3.17 (d, J=7.2 Hz 2H), 3.10 (s, 3H) 2.76-2.86 (m, 2H), 1.92-2.00(m, 5H), 1.66-1.86 (m, 6H).

Example 21: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((1-Methylcyclobutyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.0 g, 3 mmol) in DMF (10 mL) was added 1-methylcyclobutan-1-amine (0.5g, 4 mmol) and sodium bicarbonate (0.56 g, 7 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard methods to afford (1S,4S)-4-((2-((1-methylcyclobutyl) amino)-5-nitropyrimidin-4-yl) amino)cyclohexane-1-carboxamide (0.6 g, 51%) as yellow solid. MS (ESI) m/z 349[M+1]⁺.

(1S,4S)-4-((5-Amino-2-((1-methylcyclobutyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution (1S, 4S)-4-((2-((1-methylcyclobutyl)amino)-5-nitropyrimidin-4-yl) amino) cyclohexane-1-carboxamide (0.8 g, 2mmol) in ethanol (24 mL) was added palladium on carbon (0.1 g, 10% w/w)under inert atmosphere at ambient temperature. The reaction mixture wasstirred under atmospheric hydrogen pressure at ambient temperature for16 h. Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.7 g, 90%) as a brown solid. MS (ESI)m/z 319 [M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((1-methylcyclobutyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.4 g, 1 mmol) and1-chloro-3-isothiocyanatobenzene (0.2 g, 1 mmol) in THF was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.5 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclobutyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 43%) as an yellow solid. MS (ESI) m/z 454, 455 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclobutyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.2 g, 0.4 mmol) in THF (10 mL) was added drop wise lithium aluminiumhydride in THF (1.6 M, 3 mL) at 0° C. The reaction mixture was heated to50° C. for 4 h. Completion of the reaction was confirmed by UPLC. Theproduct was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine(0.040 g, 16%). MS (ESI) m/z 440, 441 [M, M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.60, 8.19 (s, 1H), 7.64 (s, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H),7.26-7.31 (t, J=8 Hz, 1H), 7.01-7.04 (m, 1H), 4.30-4.34 (m, 1H),3.20-3.22 (d, J=7.6 Hz, 2H), 2.69-2.73 (m, 2H), 2.33-2.37 (m, 2H),2.15-2.20 (m, 2H), 2.08 (brs, 1H), 1.86-1.98 (m, 4H), 1.77-1.85 (m, 4H),1.60 (s, 3H).

Example 22: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tert-pentyl)-9H-purine-2,8-diamine

(1S,4S)-4-((5-Nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in DMF (10 mL) was added sodium bicarbonate (0.17 g, 2mmol) portionwise followed by 2-methylbutane-2-amine (0.22 g, 2 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated to afford (1S,4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.6 g, 83%) as a yellow solid. MS (ESI) m/z351 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 2 mmol) in ethanol (10 mL) was added palladium on charcoal (0.06g, 10% W/M) portionwise under argon atmosphere. The reaction was stirredat ambient temperature under atmospheric hydrogen. Completion of thereaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.4 g, 90%) as a yellow solid. MS (ESI) m/z 321 [M+1]⁺.

(1S,4S)-4-8-((3-Chlorophenyl)amino-2-(tert-pentylamino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g, 1 mmol) in THF (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-chloro-3-isothiocyanatobenzene (0.27 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-8-((3-chlorophenyl)amino-2-(tert-pentylamino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.25 g, 35%) as colorless solid. MS (ESI) m/z 456 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tert-pentyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-8-((3-chlorophenyl)amino-2-(tert-pentylamino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.25 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 5 mL) at 0° C. The reaction mixture was heated to 55° C. for 1h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tert-pentyl)-9H-purine-2,8-diamine (0.04 g, 16%). MS (ESI) m/z 442 [M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.17 (s, 1H), 7.64 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.26-7.30(m, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.28-4.38 (m, 1H), 3.10 (d, J=7.2 Hz,2H), 2.68-2.72 (m, 2H), 1.93-1.99 (m, 6H), 1.75-1.87 (m, 3H), 1.48 (s,6H), 0.93 (t, J=7.6 Hz, 3H).

Example 23: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((5-Nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3.33 mmol) in DMF (10 mL) was added tetrahydro-2H-pyran-4-amine(0.37 g, 3.67 mmol) and sodium bicarbonate (0.56 g, 6.67 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and triturated with petroleum ether to afford (1S,4S)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 66%) as an off-white solid. MS (ESI) m/z 365, 366 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-nitro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 2.19 mmol) in methanol (24 mL) was added palladium on carbonunder inert atmosphere at ambient temperature. The reaction mixture wasstirred under atmospheric hydrogen at ambient temperature. Completion ofthe reaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through bed of celite, washed with methanol and concentrated toafford (1S,4S)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 82%) as a black solid. MS (ESI) m/z 335 [M+1]⁺.

(1S, 4S)-4-(8-((3-Chlorophenyl) amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 1.79 mmol) and 1-chloro-3-isothiocyanatobenzene (0.33 g, 1.97mmol) in THF was added EDCI (0.69 g, 2.04 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 36%) as an off-white solid. MS (ESI) m/z 471, 472 [M, M+1]⁺.

9-((1S, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S, 4S)-4-(8-((3-chlorophenyl)amino)-2-((tetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 0.64 mmol) in THF (10 mL) was added dropwise lithium aluminiumhydride in THF (1.6 M; 3 mL) at 0° C. and the reaction was heated at 50°C. for 8 h. Completion of the reaction was confirmed by TLC. The productwas purified via standard methods to afford 9-((1S, 4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine (50 mg, 17%). MS (ESI) m/z 456, 457 [M, M+1]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.18 (s, 1H), 7.65 (s, 1H), 7.41-7.43 (m, 1H), 7.26-7.30(m, 1H), 7.01-7.03 (m, 1H), 4.31-4.37 (m, 1H), 3.97-4.02 (m, 3H),3.56-3.62 (m, 2H), 3.14-3.16 (m, 2H), 2.69-2.80 (m, 2H), 1.93-2.06 (m,5H), 1.62-1.86 (m, 6H).

Example 24: 1-Methylcyclopentan-1-amine hydrochloride

2-Chloro-N-(1-methylcyclopentyl)acetamide

A mixture of acetic acid (0.7 mL) and sulphuric acid (0.7 mL) was addeddropwise to a stirred solution of 1-methylcyclopentan-1-ol (0.5 g, 5mmol) in chloroacetonitrile (0.54 mL, 6 mmol) at 0° C. The reaction wasstirred at ambient temperature for 3 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated and purified via standardmethods to afford 2-chloro-N-(1-methylcyclopentyl)acetamide (0.65 g,74%) as white solid. GCMS m/z 175.6

1-Methylcyclopentan-1-amine hydrochloride

To the stirred solution of 2-chloro-N-(1-methylcyclopentyl)acetamide(0.63 g, 3.59 mmol) in ethanol (5 mL) and acetic acid (1 mL) mixture wasadded thiourea (0.28 g, 3.59 mmol) at ambient temperature. The mixturewas stirred at 80° C. for 2 h. Completion of the reaction was confirmedby TLC. The product was isolated and purified via standard methods toafford 1-methylcyclopentan-1-amine hydrochloride (0.5 g) as white solid.GCMS m/z 135.64.

Example 25: 9-((1S, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((1-Methylcyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To the stirred solution of (1S, 4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino) cyclohexane-1-carboxamide (0.7 g, 2.34 mmol) in DMF (10 mL),1-methylcyclopentan-1-amine hydrochloride (0.35 g, 3.51 mmol) and sodiumbicarbonate (1.0 g, 11.71 mmol) were added at ambient temperature andthe mixture was heated to 60° C. for 16 h. Completion of the reactionwas confirmed by UPLC. The product was isolated to afford (1S, 4S)-4-((2-((1-methylcyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 60%) as off-white solid. MS (ESI) m/z 363, 364 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-((1-methylcyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((1-methylcyclopentyl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 1.38 mmol) in methanol (10 mL) was added palladium on carbon(0.15 g) under inert atmosphere at ambient temperature. The reactionmixture was stirred under atmospheric hydrogen. Completion of thereaction was confirmed by TLC. The resulting reaction mixture wasfiltered through bed of celite, washed with methanol and concentrated toafford (1S,4S)-4-((5-amino-2-((1-methylcyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g) as brown gummy solid. MS (ESI) m/z 333, 334 [M, M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((1-methylcyclopentyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((5-amino-2-((1-methylcyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g,1.51 mmol) and 1-chloro-3-isothiocyanatobenzenes (0.3 g, 1.81 mmol) inTHF was added EDCI (1.14 g, 3.01 mmol) at ambient temperature. Thereaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford (1S, 4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclopentyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.27 g, 39%) as pale yellow solid. MS (ESI)m/z 468, 469 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-(1-methylcyclopentyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.24 g, 0.51 mmol) in THF (10 mL) was added dropwise lithium aluminiumhydride in THF (1.6 M; 3 mL) at 0° C. and heated at 50° C. for 8 h.Completion of the reaction was confirmed by TLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine (70 mg; 30%). MS (ESI) m/z 454.2, 455.2 [M, M+1]+. ¹H NMR (400MHz, CD₃OD): δ 8.56 (brs, 1H), 8.19 (brs, 1H), 7.71 (brs, 1H), 7.45 (d,J=8.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.04 (d, J=8 Hz, 1H), 4.36-4.42 (m,1H), 3.28 (d, J=7.6 Hz, 2H), 2.71-2.80 (m, 2H), 2.23-2.26 (m, 2H), 2.17(brs, 1H), 1.94-2.01 (m, 4H), 1.75-1.87 (m, 9H), 1.66 (s, 3H).

Example 26: 9-((1S, 4S)-4-(Aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidine-4-yl)amino)cyclohexane-1-carboxamide(2.0 g, 6 mmol) in DMF (10 mL) was added sodium carbonate (1.9 g, 18mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-aminehydrochloride (1.2 g, 8 mmol) at ambient temperature. The reactionmixture was stirred for 4 h. Completion of the reaction was confirmed byUPLC. The product was isolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (1.5 g, 66%) as a yellow solid. MS (ESI)m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 2 mmol) in ethanol (10 mL) was added palladium on charcoal (0.07g, 10% W/M) portionwise under argon atmosphere. The reaction was stirredat ambient temperature under atmospheric hydrogen. Completion of thereaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 71%) as a yellow solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(8-((2,3-Difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.25 g, 1 mmol) in THF (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.3 g, 1.5 mmol) and1,2-difluoro-3-isothiocyanatobenzene (0.12 g, 1 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((2,3-difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclo

hexane-1-carboxamide (0.2 g, 62%) as off-white solid. MS (ESI) m/z 486[M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of ((1S, 4S)-4-(8-((2,3-difluorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.2 g, 0.5 mmol) in THF (3 mL) was added lithium aluminum hydride inTHF (1.6 M; 1 mL) at 0° C. The reaction mixture was heated to 55° C. for1 h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-H-pyran-4-yl)-9H-purine-2,8-diamine(0.03 g, 16%). MS (ESI) m/z 472 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.10(s, 1H), 7.30 (m, 1H), 7.08-7.14 (m, 1H), 7.0-7.02 (m, 1H), 4.4-4.6 (m,1H), 3.7-3.8 (m, 4H), 3.15 (d, J=7.2 Hz, 2H), 2.60-2.69 (m, 2H),2.40-2.42 (m, 2H), 1.92-2.05 (m, 5H) 1.72-1.80 (m, 5H), 1.6 (s, 3H),

Example 27: N-(((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide

N-(((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide

To a solution of 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 0.1 mmol) in dry chloroform (10 mL) was added acetic anhydride(0.01 g, 0.1 mmol) at 0° C. under nitrogen. The reaction mixture wasstirred at ambient temperature for 3 h. Completion of the reaction wasconfirmed by TLC. The product was purified via standard methods toafford N-(((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide(0.04 g, 74%). MS (ESI) m/z 512.2, 513.4 [M, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.20 (s, 1H), 7.70 (s, 1H), 7.45 (d, J=8 Hz, 1H), 7.29-7.33(m, 1H), 7.04 (d, J=8 Hz, 1H), 4.29-4.36 (m, 1H), 3.77-3.79 (m, 4H),3.47-3.49 (d, J=7.6 Hz 2H), 2.75-2.78 (m, 2H), 2.33-2.37 (m, 2H),1.83-1.99 (m, 6H), 1.72-1.82 (m, 6H), 1.61 (s, 3H).

Example 28: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium carbonate (5.3 g, 50mmol) portionwise followed by 4-methyl-tetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred for 16h. Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (70 mL, 9:1) was added iron powder (8.4g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

3-Chloro-5-isothiocyanatopyridine

To a stirred solution of 5-chloropyridin-3-amine (1 g, 8 mmol) indichloromethane (25 ml) and saturated sodium bicarbonate solution (25mL) was added dropwise thiophosgene (1 g, 9 mmol) at 0° C. The reactionmixture was stirred at ambient temperature for 1 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard purification methods to afford3-chloro-5-isothiocyanatopyridine (0.6 g, 46%) as a pale yellow liquid.MS (ESI) m/z 170 [M+1]⁺.

(1S,4S)-4-(8-((5-Chloropyridin-3-yl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and3-chloro-5-isothiocyanatopyridine (0.4 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)-4-(8-((5-chloropyridin-3-yl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.27 g, 33%) as pale yellow solid. MS(ESI) m/z 485, 486 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((5-chloropyridin-3-yl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.27 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 5 mL) at 0° C. The reaction mixture was heated to 50° C. for 3h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine (0.045 g, 18%). MS (ESI) m/z 471.2, 472.2 [M, M+1]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.67 (m, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.20 (m,1H), 4.35-4.41 (m, 1H), 3.77-3.80 (m, 4H), 3.08 (d, J=7.4 Hz, 2H),2.65-2.74 (m, 2H), 2.39-2.42 (m, 2H), 2.02-1.99 (m, 3H), 1.77-1.88 (m,6H), 1.62 (s, 3H).

Example 29: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(2-(trifluoromethyl)pyridin-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 17 mmol) in DMF (10 mL) was added sodium carbonate (5.3 g, 50mmol) portionwise followed by 2-methylbutane-2-amine (3 g, 20 mmol) atambient temperature. The reaction mixture was stirred same temperaturefor 16 h. Completion of the reaction was confirmed by LCMS. The productwas isolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (50 mL, 1:1) was added iron powder (8.4g, 80 mmol) followed by ammonium chloride (0.8 g, 8 mmol). The reactionmixture was heated to 85° C. Completion of the reaction was confirmed byLCMS. The resulting reaction mixture was filtered through a bed ofcelite, washed with ethyl acetate and concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 95%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

4-Isothiocyanato-2-(trifluoromethyl)pyridine

To a stirred solution of 2-(trifluoromethyl)pyridine-4-amine (1 g, 6mmol) in dichloromethane (25 mL) was added saturated sodium bicarbonatesolution (25 mL). Thiophosgene (0.84 g, 7 mmol) was added dropwise andthe resulting reaction mixture was stirred at ambient temperature for 1h. Completion of the reaction was confirmed by UPLC. The product wasisolated to afford 4-isothiocyanato-2-(trifluoromethyl)pyridine (0.6 g,50%) as a light yellow liquid. MS (ESI) m/z 205 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((2-(trifluoromethyl)pyridin-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.7 g, 3 mmol) and4-isothiocyanato-2-(trifluoromethyl)pyridine (0.35 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification method to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2-(trifluoromethyl)pyridin-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 33%) as an off-white solid. MS (ESI) m/z 519 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((2-(trifluoromethyl)pyridin-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 1 mmol) in diethyl ether (10 mL) was added lithium aluminumhydride in THF (2.4 M; 5 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 2 h. Completion of the reaction was confirmedby UPLC. The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine. MS (ESI) m/z 506 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.50 (d,J=8 Hz, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 7.87-7.89 (m, 1H), 4.39-4.45(m, 1H), 3.76-3.84 (m, 4H), 3.24 (d, J=7.6 Hz, 2H), 2.67-2.70 (m, 2H),2.46-2.50 (m, 2H), 2.14 (brs, 1H), 1.91-2.01 (m, 4H), 1.72-1.84 (m, 4H),1.61 (s, 3H).

Example 30:9-(3-Aminocyclobutyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

tert-Butyl(3-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (0.3 g, 2 mmol)and DIPEA (1 mL, 5 mmol) in 2-propanol (10 mL) was added tert-butyl(3-aminocyclobutyl)carbamate (0.31 g, 3 mmol) portionwise at 0° C. undernitrogen. The reaction mixture was slowly warmed to ambient temperatureand stirred for 5 h. Completion of the reaction was confirmed by UPLC.The product was isolated to affordtert-butyl(3-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate (0.4 g, 75%) as yellow solid. MS (ESI) m/z 346.2 [M+2]⁺.

tert-Butyl(3-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate

To a stirred solution oftert-butyl(3-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate(0.40 g 2 mmol) in DMF (10 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.14 g, 1 mmol) and sodiumbicarbonate (0.292 g, 3 mmol) at ambient temperature. The reactionmixture was stirred at ambient temperature for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford tert-butyl(3-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate(0.38 g, 77%) as yellow solid. MS (ESI) m/z 423 [M+1]⁺.

tert-Butyl(3-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclobutyl)carbamate

To a stirred solution of tert-butyl(3-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclobutyl)carbamate(0.38 g, 1 mmol) in ethanol:water (50 mL, 3:1) was added iron powder(0.50 g, 1 mmol) and ammonium chloride (0.05 g, 1 mmol) at ambienttemperature. The reaction mixture was heated to 80° C. for 6 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to affordtert-butyl(3-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclobutyl)carbamate(0.37 g) as a brown solid. MS (ESI) m/z 394.4 [M+2]⁺.

tert-Butyl(3-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclobutyl)carbamate

To a stirred solution of tert-butyl(3-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclobutyl)carbamate(0.37 g, 1 mmol) and 1-chloro-3-isothiocyanatobenzene (0.181 g, 1 mmol)in THF was added EDCI (0.340 g, 2 mmol) at ambient temperature. Thereaction mixture was heated to 60° C. for 6 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford tert-butyl (3-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclobutyl)carbamate(0.11 g, 27%) as an off-white solid. MS (ESI) m/z 427, 429 [M, M+2]⁺.

9-(3-(Aminocyclobutyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl (3-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclobutyl)carbamate(0.11 g, 0.5 mmol) in DCM (10 mL) was added HCl in dioxane (2 mL) at 0°C. The reaction mixture was stirred at ambient temperature for 2 h.Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford9-(3-(aminocyclobutyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(10 mg, 12%). MS (ESI) m/z 428.2, 429.2 [M, M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.26 (s, 1H), 7.63 (s, 1H), 7.29-7.39 (m, 2H), 7.03 (dd, J=1.6Hz & 8.8 Hz, 1H),5.21-5.25 (m, 1H), 4.10-4.20 (m, 1H), 3.73-3.84 (m,4H), 3.46-3.51 (m, 2H), 2.42-2.55 (m, 4H), 1.73-1.80 (m, 2H) 1.59 (s,3H).

Example 31: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium carbonate (5.3 g, 60mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred atambient temperature for 16 h. Completion of the reaction was confirmedby UPLC. The product was isolated via standard purification methods toafford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (60 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting mixturewas filtered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(8-((3-Chloro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (1:1; 20 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-chloro-3-isothiocyanato-5-(trifluoromethyl)benzene (0.5 g, 2 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-(8-((3-chloro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 42%) as pale yellow solid. MS (ESI) m/z 552, 553 [M, M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chloro-5-(trifluoromethyl)phenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 5 mL) at 0° C. The reaction mixture was stirred at ambienttemperature for 3 h. Completion of the reaction was confirmed by UPLC.The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.05 g, 15%). MS (ESI) m/z 538.2, 539.2 [M+, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.28 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.31 (s, 1H),4.33-4.39 (m, 1H), 3.76-3.82 (m, 4H), 3.05 (d, J=7.2 Hz, 2H), 2.65-2.74(m, 2H), 2.38-2.41 (m, 2H), 1.98-2.02 (m, 3H), 1.75-1.91 (m, 6H), 1.62(s, 3H).

Example 32: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium carbonate (5.3 g, 50mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred atambient temperature for 16 h. Completion of the reaction was confirmedby UPLC. The product was isolated via standard purification method toafford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (70 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-isothiocyanato-3-(trifluoromethoxy)-benzene (0.4 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.4 g, 43%) as pale yellow solid. MS (ESI) m/z 534 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.27 g, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 5 mL) at 0° C. The reaction mixture was heated to 50° C. for 3h. Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.09 g, 23%). MS (ESI) m/z 520.2 [M+1]+. ¹H NMR (400 MHz, CD₃OD): δ8.22 (s, 1H), 7.62 (s, 1H), 7.58 (dd, J=1.4 Hz & 8.2 Hz, 1H),7.40-7.44(m, 1H), 6.93-6.95 (m, 1H), 4.31-4.39 (m, 1H), 3.77-3.79 (m, 4H), 2.97(d, J=7.5 Hz, 2H), 2.65-2.74 (m, 2H), 2.34-2.38 (m, 2H), 1.98-2.01 (m,2H), 1.85-1.87 (m, 7H), 1.62 (s, 3H).

Example 33: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(5 g, 20 mmol) in DMF (50 mL) was added sodium bicarbonate (5.3 g, 50mmol) portionwise followed by 4-methyltetrahydro-2H-pyran-4-amine (3 g,20 mmol) at ambient temperature. The reaction mixture was stirred for 16h. Completion of the reaction was confirmed by UPLC. The product wasisolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 50%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.2 g, 8 mmol) in ethanol:water (66 mL, 10:1) was added iron powder(8.4 g, 80 mmol) and ammonium chloride (0.5 g, 8 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 16 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(2.8 g, 90%) as a violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in THF:DMF (20 mL, 1:1) was added1-ethyl-3-(3-dimethylamino propyl)carbodiimide (0.7 g, 3 mmol) and1-isothiocyanato-4-(trifluoromethoxy)benzene (0.5 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 50° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.5 g, 54%) as white solid. MS (ESI) m/z 534 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethoxy)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(400 mg, 1 mmol) in THF (3 mL) was added lithium aluminum hydride in THF(1.6 M; 6 mL) at 0° C. The reaction mixture was stirred at ambienttemperature for 2 h. Completion of the reaction was confirmed by UPLC.The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine(0.08 g, 20%). MS (ESI) m/z 521.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.17 (s, 1H), 7.65 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 4.31-4.38 (m,1H), 3.77-3.82 (m, 4H), 2.97 (d, J=7.2 Hz, 2H), 2.68-2.74 (m, 2H),2.34-2.38 (m, 2H), 1.98-2.02 (m, 2H), 1.73-1.91 (m, 7H), 1.62 (s, 3H).

Example 34: N8-(3-Chlorophenyl)-9-((1S,4S)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

tert-Butyl ((1S, 4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate

To a solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (2 g,8.2 mmol) in dry DCM (30 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g, 16 mmol), HOBt(1.1 g, 16 mmol), DIPEA (2.12 g, 33 mmol) and dimethyl amine (1.35 g, 33mmol, 2.4M solution in THF) at 0° C. and stirred for 16 h at ambienttemperature. Completion of the reaction was confirmed by TLC. Theproduct was isolated via standard purification methods to affordtert-butyl ((1S, 4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate (2 g,90%) as gummy solid. GCMS m/z 270 [M]⁺.

(1S, 4S)-4-Amino-N, N-dimethylcyclohexane-1-carboxamide

To a stirred solution of tert-butyl ((1S,4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate (2 g, 8 mmol) in ethanol(10 mL) was added dropwise HCl in 1, 4-dioxane in (4.5 M, 5 mL) at 0° C.The reaction mixture was stirred at ambient temperature for 4 h.Completion of the reaction was confirmed by TLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-amino-N,N-dimethylcyclohexane-1-carboxamide (1.2 g, 80%) as whitesolid. GCMS m/z 170 [M]⁺.

(1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide

To a solution of (1S, 4S)-4-amino-N, N-dimethylcyclohexane-1-carboxamide(1.9 g, 10 mmol) in IPA was added 2,4-dichloro-5-nitropyrimidine (1.9 g,10 mmol) and DIPEA (3.7 g, 30 mmol) at ambient temperature. The reactionwas stirred for 2 h at 50° C. Completion of the reaction was confirmedby UPLC. The product was isolated via standard purification methods toafford (1S, 4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide (1 g, 30%). MS (ESI) m/z 327, 328[M, M+1]⁺.

(1S,4S)—N,N-Dimethyl-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.28 g, 2 mmol) in DMF (10 mL) was added 4-methyltetrahydro-2H-pyran-4-amine (0.5 g, 2 mmol), sodium carbonate (0.5 g, 5mmol). The reaction mass was stirred at ambient temperature for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1S,4S)—N,N-dimethyl-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.23 g, 37%) as a pale brown solid MS (ESI) m/z 407 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide

To a stirred solution of (1S,4S)—N,N-dimethyl-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.23 g, 1 mmol) in ethanol (10 mL) was addedpalladium on carbon (30 mg, 10% W/M) under argon atmosphere. Reactionmixture was stirred at ambient temperature under atmospheric hydrogen.Completion of the reaction was confirmed by UPLC. The product wasisolated by standard purification methods to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.2 g, 90%) as violet solid MS (ESI) m/z 377 [M+1]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-N,N-dimethylcyclohexane-1-carboxamide

A solution of (1S,4S)-4-((5-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.35 g, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g,2 mmol) and 1-chloro-3-isothiocyanatobenzene (0.19 g, 1.2 mmol) in THF(5 mL) was mixed at ambient temperature. The reaction was heated to 50°C. for 4 h. Completion of the reaction was confirmed by UPLC. Theproduct was isolated by standard purification methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-N,N-dimethylcyclohexane-1-carboxamide (0.2 g, 42%) as an off-white solidMS (ESI) m/z 511, 512 [M, M+1]⁺.

N8-(3-Chlorophenyl)-9-((1S,4S)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)-N,N-dimethylcyclohexane-1-carboxamide(0.17 g, 0.33 mmol) in THF (3 mL) was added lithium aluminium hydride inTHF (1.6 M; 5 mL) at 0° C. The reaction was heated at 50° C. for 1 h.Completion of the reaction was confirmed by TLC. The reaction mixturewas quenched with 10% NaOH solution and water (10 mL, 1:1) and extractedwith ethyl acetate. The product was purified by standard methods toafford N8-(3-chlorophenyl)-9-((1S,4S)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.060 g, 33%). MS (ESI) m/z 498.4, 499.4 [M⁺, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.34 (brs, 1H, NH proton), 8.21 (s, 1H), 7.63-7.64 (m, 1H),7.40-7.42 (m, 1H), 7.27-7.31 (m, 1H), 7.02-7.04 (m, 1H), 4.29-4.35 (m,1H), 3.72-3.82 (m, 4H), 3.13 (d, J=6.4 Hz, 2H), 2.79 (s, 6H), 2.57-2.67(m, 2H), 2.38-2.41 (m, 2H), 2.23 (brs, 1H), 1.75-1.97 (m, 8H), 1.00 (s,3H).

Example 35: 9-((1R,4R)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

(1R, 4R)-4-((tert-Butoxycarbonyl)amino)cyclohexane-1-carboxylic acid

To a solution of (1R, 4R)-4-aminocyclohexane-1-carboxylic acid (2 g, 13mmol) in N, N-dimethyl formamide (10 mL) was added Boc anhydride (5 g,20 mmol) and triethylamine (4.2 g, 13 mmol). Then, the resultingreaction mixture was stirred at ambient temperature for 18 h. Completionof the reaction was confirmed by GCMS. The product was isolated toafford (1R, 4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylicacid (2.5 g, 95%) as a pale yellow solid. GCMS m/z 243 [M]⁺.

tert-Butyl((1R, 4R)-4-carbamoylcyclohexyl)carbamate

To a solution of (1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (2.5 g,10 mmol) in dry THF (10 mL) was added ethyl chloroformate (1.6 g, 15mmol) and triethyl amine (3.1 g, 30 mmol) at 0° C. and the reaction wasstirred at ambient temperature for 3 h. Completion of the reaction wasconfirmed by TLC. The reaction was quenched with ammonia in THF (10 Msolution). The product was isolated via standard methods to affordtert-butyl((1R, 4R)-4-carbamoylcyclohexyl)carbamate (1.4 g, 50%) aswhite solid. GCMS m/z 242 [M]⁺.

(1R, 4R)-4-Aminocyclohexane-1-carboxamide

To a stirred solution of tert-butyl ((1R,4R)-4-carbamoylcyclohexyl)carbamate (1.4 g, 0.88 mmol) in ethanol (10mL) was added dropwise HCl in 1, 4-dioxane (4.5 M, 5 mL) at 0° C. Thereaction mixture was stirred for 4 h. Completion of the reaction wasconfirmed by TLC. The product was isolated and purified via standardmethods to afford (1R, 4R)-4-aminocyclohexane-1-carboxamidehydrochloride(0.8 g, 96%) as white solid. GCMS m/z 142 [M]⁺.

(1R,4R)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a solution of (1R, 4R)-4-aminocyclohexane-1-carboxamidehydrochloride(0.8 g, 4 mmol) in IPA (20 mL) was added 2,4-dichloro-5-nitropyrimidine(1 g, 4 mmol) and DIPEA (1.7 g, 14 mmol) at ambient temperature.Reaction mixture temperature was raised to 50° C. and stirred for 2 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification methods to afford (1R,4R)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.8 g, 59%). MS (ESI) m/z 299, 300 [M, M+1]⁺.

(1R,4R)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1R,4R)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in DMF (10 mL) was added4-methyltetrahydro-2H-pyran-4-amine (0.3 g, 2 mmol) and sodium carbonate(0.6 g, 5 mmol). The reaction mixture was stirred at ambient temperaturefor 16 h. Completion of the reaction was confirmed by UPLC. The productwas isolated via standard purification methods to afford (1R,4R)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.25 g, 33%) as pale yellow solid. MS (ESI) m/z 378, 379 [M, M+1]⁺.

(1R,4R)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1R,4R)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.25 g, 1 mmol) in ethanol (10 mL) was added palladium on carbon (0.003g, 10% w/w) under argon atmosphere. The reaction mixture was stirredunder atmospheric hydrogen pressure at ambient temperature for 16 h.Completion of the reaction was confirmed by TLC. The product wasisolated by standard purification method to afford (1R,4R)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.2 g, 90%) as violet solid. MS (ESI) m/z 349 [M+1]⁺.

(1R,4R)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1R,4R)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.35 g, 1 mmol) and 1-chloro-3-isothiocyanatobenzene (0.2 g, 1.2 mmol)was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.39 g, 2mmol) in THF (5 mL) at ambient temperature. The reaction was heated to50° C. for 4 h. Completion of the reaction was confirmed by UPLC. Theproduct was isolated by standard purification methods to afford (1R,4R)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.25 g, 51%) as an off-white solid. MS (ESI) m/z 484, 485 [M, M+1]⁺.

9-((1R,4R)-4-(Aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution (1R,4R)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.25 g, 0.5 mmol) in THF (3 mL) was added lithium aluminum hydride inTHF (1.6 M, 5 mL) at 0° C. and the reaction was heated at 50° C. for 1h. Completion of the reaction was confirmed by TLC. The product waspurified by standard methods to afford 9-((1R,4R)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine (0.05 g, 21%) as an off-white solid. MS (ESI) m/z 470.2, 471.2[M, M+1]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.25 (m, 1H), 7.90 (s, 1H), 7.64(d, J=8 Hz, 1H), 7.29-7.33 (m, 1H), 6.97-6.99 (dd, J=1.6 Hz, 8 Hz, 1H),5.86 (s, 1H) 4.34-4.40 (m, 1H), 3.57-3.70 (m, 4H), 2.49-2.66 (m, 4H),2.27-2.32 (m, 2H), 1.92-1.95 (m, 2H), 1.83-1.86 (m, 2H), 1.64-1.71 (m,2H), 1.49 (s, 3H), 1.26-1.40 (m, 1H), 1.12-1.18 (m, 2H).

Example 36: N-((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)acetamide

N-((1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)acetamide

To a solution of 9-((1S,4S)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.2 g, 0.43 mmol) in dry chloroform (10 mL) was added acetic anhydride(0.053 g, 0.52 mmol) at 0° C. under nitrogen. The reaction mixture wasstirred at ambient temperature for 3 h. Completion of the reaction wasconfirmed by TLC. The product was purified via standard methods toafford N-((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)acetamide(0.04 g, 74%). MS (ESI) m/z 498.2, 499.2 [M, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.20 (s, 1H), 7.66 (s, 1H), 7.43 (dd, J=1.6 Hz, 8.4 Hz, 1H),7.27-7.31 (m, 1H), 7.02-7.05 (m, 1H), 4.30-4.36 (m, 1H), 4.01 (brs, 1H),3.72-3.83 (m, 4H), 2.67-2.77 (m, 2H), 2.38-2.41 (m, 2H), 2.12-2.16 (m,2H), 2.05 (s, 3H), 1.72-1.80 (m, 6H), 1.59 (s, 3H).

Example 37: ((1R,4R)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol

((1R, 4R)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of 2,4-dichloro-5-nitropyrimidine (0.6 g, 3 mmol)in THF (10 mL) was added DIPEA (0.4 g, 3 mmol) dropwise followed by((1R, 4R)-4-aminocyclohexyl)methanol (0.4 g, 3 mmol) at ambienttemperature. The reaction mixture was stirred at ambient temperature for4 h. Completion of the reaction was confirmed by UPLC. The product wasisolated to afford ((1R,4R)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.3 g,33%) as a yellow solid. MS (ESI) m/z 287 [M+1]⁺.

((1R,4R)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of ((1R,4R)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.3 g,1 mmol) in DMF (10 mL) was added sodium carbonate (0.2 g, 2 mmol)portionwise followed by 4-methyltetrahydro-2H-pyran-4-aminehydrochloride(0.1 g, 1 mmol) at ambient temperature. The reaction mixture was stirredfor 4 h at ambient temperature. Completion of the reaction was confirmedby UPLC. The product was isolated to afford ((1R,4R)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.25 g, 64%) as a yellow solid. MS (ESI) m/z 366 [M+1]⁺.

((1R,4R)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol

To a stirred solution of ((1R,4R)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)methanol (0.25 g, 1 mmol)in ethanol:water (10 mL, 2:2) was added iron powder (0.4 g, 7 mmol)portionwise followed by ammonium chloride (0.04 g, 1 mmol) at ambienttemperature. The reaction mixture was heated to 80° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford ((1R,4R)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol(0.2 g) as an off-white solid. MS (ESI) m/z 336 [M+1].

((1R,4R)-4-(8-((3-Chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol

To a stirred solution of ((1R,4R)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanol(0.25 g, 1 mmol) in THF (10 mL) was added to1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.2 g, 1 mmol) and1-isothiocyanato-3-chlorobenzene (0.1 g, 1 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was via standard methods toafford ((1R,4R)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methanol(0.06 g, 40%). MS (ESI) m/z 471 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.20(s, 1H), 7.71 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.28-7.32 (m, 1H), 7.03(d, J=8.0 Hz, 1H), 4.30-4.36 (m, 1H), 3.73-3.81 (m, 4H), 3.45-3.47 (m,2H), 2.64-2.73 (m, 2H), 2.35-2.39 (m, 2H), 1.94-2.04 (m, 4H), 1.74-1.81(m, 2H), 1.61-1.62 (m, 1H), 1.57 (s, 3H), 1.19-1.23 (m, 2H).

Example 38: 9-((1S,4S)-4-Aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

tert-Butyl ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of 2,4-dichloro-5-nitropyrimidine (1 g, 5 mmol) inIPA (10 mL) was added tert-butyl ((S, 4S)-4-aminocyclohexyl)carbamate(1.3 g, 6 mmol) and DIPEA (2 g, 15 mmol) at 0° C. The reaction mixturewas stirred for 1 h. Completion of the reaction was confirmed by UPLC.The product was isolated and triturated with petroleum ether to affordtert-butyl ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (1 g,52%) as a yellow solid. MS (ESI) m/z 371, 372 [M, M+1]⁺.

tert-Butyl ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution tert-butyl-((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (1 g,3 mmol) in DMF (20 mL) was added 4-methyltetrahydro-2H-pyran-4-amine(0.5 g, 3 mmol) and sodium carbonate (0.7 g, 8 mmol) under inertatmosphere at ambient temperature. The reaction mixture was stirred for16 h. Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford tert-butyl((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate(1 g, 81%) as a yellow solid. MS (ESI) m/z 451 [M+1]⁺.

tert-Butyl ((1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution tert-butyl ((1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate(1 g, 2 mmol) in ethanol:water (30 mL, 10:1) was added iron powder (1.2g, 20 mmol) and ammonium chloride (0.14 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. and maintainedfor 12 h. Completion of the reaction was confirmed by UPLC. The productwas isolated via standard methods to afford tert-butyl ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate(0.9 g, 95%) as a brown solid. MS (ESI) m/z 421 [M+1]⁺.

tert-Butyl-((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)carbamate (0.9 g, 2 mmol) and 1-chloro-3-isothiocyanatobenzene (0.5 g,2.5 mmol) in THF was added EDCI (0.8 g, 4 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford tert-butyl((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)carbamate(0.45 g, 38%) as a yellow solid. MS (ESI) m/z 556, 557 [M, M+1]⁺.

9-((1S,4S)-4-Aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl-((1S, 4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)carbamate (0.3 g, 0.13 mmol) in ethanol (10 mL) was added HCl in 1,4-dioxane (4.5 M, 5 mL) dropwise at 0° C. The reaction was stirred atambient temperate for 4 h. Completion of the reaction was confirmed byTLC. The product was purified via standard methods to afford 9-((1S,4S)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.1 g, 30%). MS (ESI) m/z 456.2, 457.2 [M, M+1]⁺. ¹HNMR (400 MHz,CD₃OD): δ 8.21 (s, 1H), 7.71 (s, 1H), 7.45 (d, J=8 Hz, 1H), 7.29-7.33(m, 1H), 7.04 (dd, J=1.2 Hz & 8 Hz, 1H),4.35-4.44 (m, 1H), 3.72-3.81 (m,5H), 2.77-2.81 (m, 2H), 2.45-2.48 (m, 2H), 1.90-2.04 (m, 4H), 1.70-1.83(m, 4H) 1.57 (s, 3H).

Example 39: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((2-chloro-5-nitropyrimidine-4-yl)amino)cyclohexane-1-carboxamide (2.0 g, 6 mmol) in DMF(10 mL) was added sodium carbonate (1.9 g, 18 mmol) portionwise followedby 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.2 g, 8 mmol) atambient temperature. The reaction mixture was stirred for 4 h at ambienttemperature. Completion of the reaction was confirmed by UPLC. Theproduct was isolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.5 g, 66%) as a yellow solid. MS (ESI) m/z 379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 2 mmol) in ethanol (10 mL) was added palladium on charcoal (0.07g, 10% w/m) portionwise under argon atmosphere. The reaction was stirredat ambient temperature under atmospheric hydrogen. Completion of thereaction was confirmed by UPLC. The resulting reaction mixture wasfiltered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 71%) as a yellow solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 1 mmol) in THF (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-isothiocyanato-3-(trifluoromethyl)benzene (0.25 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 42%) as an off-white solid. MS (ESI) m/z 517 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.25 g, 1 mmol) in diethylether (3 mL) wasadded lithium aluminum hydride in THF (1.6 M; 5 mL) at 0° C. Thereaction mixture was stirred at ambient temperature for 4 h. Completionof the reaction was confirmed by UPLC. The product was purified viastandard methods to afford 9-((1S, 4S)-4-(amino methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.06 g, 26%). MS (ESI) m/z 504 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.60(s, 1H), 8.24 (s, 1H), 7.96 (brs, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.55(m, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.38-4.42 (m, 1H), 3.75-3.85 (m, 4H),3.24 (d, J=7.6 Hz, 2H), 2.65-2.71 (m, 2H), 2.45-2.49 (m, 2H), 2.11-2.14(m, 1H), 1.98-2.0 (m, 2H), 1.72-1.94 (m, 6H), 1.61 (s, 3H).

Example 40: 9-((1S,4S)-4-Aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

tert-Butyl ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (0.8 g, 4 mmol)and DIPEA (2 mL, 12 mmol) in IPA (10 mL) was added portionwisetert-butyl ((1S, 4S)-4-aminocyclohexyl) carbamate (0.8 g, 4 mmol) at 0°C. under nitrogen. The reaction mixture was slowly warmed to ambienttemperature and stirred for 1 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated to afford tert-butyl ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl) aminocyclohexyl)carbamate (1 g)as yellow solid. MS (ESI) m/z 372, 373 [M, M+1]⁺.

tert-Butyl ((1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (1 g,3 mmol) in DMF (12 mL) was added tert butylamine (0.5 g, 7 mmol) andsodium bicarbonate (0.4 g, 5 mmol) at ambient temperature. The reactionmixture was heated to 60° C. for 4 h. The product was isolated andpurified via standard methods to afford tert-butyl ((1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate(0.9 g, 65%) as yellow solid. MS (ESI) m/z 409 [M+1]⁺.

tert-Butyl ((1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate(0.9 g, 2 mmol) in ethanol:water (15 mL, 3:1) was added iron powder (1g, 22 mmol) and ammonium chloride (0.1 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 2 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to tert-butyl ((1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate (0.8 g, 90%) as a brown solid. MS (ESI) m/z379 [M+1]⁺.

tert-Butyl ((1S,4S)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate(0.7 g, 2 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.4 g,2 mmol) in THF was added EDCI (0.71 g, 4 mmol) at ambient temperature.The reaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford tert-butyl ((1S,4S)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate(0.35 g, 35%) as an off-white solid. MS (ESI) m/z 548 [M+1]⁺.

9-((1S,4S)-4-Aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl ((1S,4S)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate(0.35 g, 0.64 mmol) in methanol (10 mL) was added HCl in dioxane (5 mL)at 0° C. The reaction mixture was stirred ambient temperature for 16 h.Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford 9-((1S,4S)-4-aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.28 g, 98%). MS (ESI) m/z 448 [M+1]+. ¹H NMR (400 MHz, CD₃OD): δ 8.21(s, 1H), 7.95 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.52-7.56 (m, 1H), 7.33(d, J=7.7 Hz, 1H), 4.40-4.46 (m, 1H), 3.37 (brs, 1H), 2.82-2.86 (m, 2H),1.97-2.02 (m, 4H), 1.83-1.86 (m, 2H), 1.53 (s, 9H).

Example 41: 9-((1R,4R)-4-Aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

tert-Butyl ((1R,4R)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1R,4R)-4-((2-chloro-5-nitropyrimidin-4-yl) amino)cyclohexyl)carbamate (1 g,2.7 mmol) in DMF (10 mL) was added tert-butylamine (0.39 g, 5.4 mmol)and sodium bicarbonate (0.34 g, 4 mmol) at ambient temperature. Thereaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford tert-butyl ((1R,4R)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate(0.6 g, 55%) as yellow solid. MS (ESI) m/z 409 [M+1]⁺.

tert-Butyl ((1R,4R)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1R,4R)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexyl)carbamate (0.6 g, 1.47 mmol) in ethanol:water (10 mL,3:1) was added iron powder (0.83 g, 15 mmol) and ammonium chloride (0.08g, 1.47 mmol) at ambient temperature. The reaction mixture was heated to85° C. for 2 h. Completion of the reaction was confirmed by UPLC. Theresulting reaction mixture was filtered through bed of celite, washedwith ethyl acetate and concentrated to afford tert-butyl ((1R,4R)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate(0.6 g, 99%) as a brown solid. MS (ESI) m/z 379 [M+1]⁺.

tert-Butyl ((1R,4R)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate

To a stirred solution of tert-butyl ((1R,4R)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexyl)carbamate(0.6 g, 1.5 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.3g, 1.5 mmol) in THF was added EDCI (0.6 g, 3 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford tert-butyl ((1R,4R)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate (0.4 g, 50%) as an off-whitesolid. MS (ESI) m/z 546 [M−1]⁺.

9-((1R,4R)-4-Aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl ((1R,4R)-4-(2-(tert-butylamino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)carbamate (0.4 g, 0.7 mmol) inmethanol (10 mL) was added HCl in dioxane (5 mL) at 0° C. The reactionmixture was stirred at ambient temperature for 16 h. Completion of thereaction was confirmed by UPLC. The product was purified via standardmethods to afford 9-((1R,4R)-4-aminocyclohexyl)-N2-(tert-butyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(120 mg, 37%). MS (ESI) m/z 448 [M+1]+. ¹H NMR (400 MHz, CD₃OD): δ 8.18(s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.51-7.55 (m, 1H), 7.32(d, J=7.8 Hz, 1H), 4.35-4.42 (m, 1H), 2.77-2.91 (m, 3H), 2.07-2.10 (m,2H), 1.93-1.96 (m, 2H), 1.52 (s, 9H), 1.36-1.42 (m, 2H).

Example 42: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((2-chloro-5-nitropyrimidine-4-yl)amino)cyclohexane-1-carboxamide (2.0 g, 6 mmol) in DMF(10 mL) was added sodium carbonate (1.9 g, 18 mmol) portionwise followedby 4-methyltetrahydro-2H-pyran-4-aminehydrochloride (1.2 g, 8 mmol) atambient temperature. The reaction mixture was stirred at ambienttemperature for 4 h. Completion of the reaction was confirmed by UPLC.The product was isolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (1.5 g, 66%) as a yellow solid. MS (ESI) m/z379 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 2 mmol) in ethanol (10 mL) was added palladium on charcoal (0.07g, 10% W/M) portionwise under argon atmosphere. The reaction was stirredat ambient temperature under atmospheric hydrogen atmosphere. Completionof the reaction was confirmed by UPLC. The resulting reaction mixturewas filtered through a bed of celite, washed with ethyl acetate andconcentrated to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 71%) as a yellow solid. MS (ESI) m/z 349 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 1 mmol) in THF (10 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g, 3 mmol) and1-isothiocyanato-3-(trifluoromethyl)benzene (0.25 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.3 g, 42%) as an off-white solid. MS (ESI) m/z 517 [M+1]⁺.

(1S,4S)-4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.25 g, 1 mmol) in pyridine (5 mL) was addedphosphorus oxychloride (0.5 ml) dropwise at 0° C. The reaction mixturewas stirred at ambient temperature for 4 h. Completion of the reactionwas confirmed by UPLC. The product was isolated and purified viastandard methods to afford (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.2 g, 74%) as off-white solid. MS (ESI) m/z 499 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.3 g, 1 mmol) in diethylether (3 mL) wasadded lithium aluminum hydride in THF (1.6 M; 2 mL) at 0° C. Thereaction mixture was stirred at ambient temperature for 4 h. Completionof the reaction was confirmed by UPLC. The product was purified viastandard methods to afford 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.04 g, 15%). MS (ESI) m/z 504 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.25(s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.38-4.44 (m,1H), 3.75-3.85 (m, 4H), 3.22 (d, J=7.6 Hz, 2H), 2.68-2.71 (m, 2H),2.45-2.48 (m, 2H), 2.11-2.14 (m, 1H), 1.98-2.00 (brs, 2H), 1.90-1.95 (m,4H), 1.76-1.84 (m, 4H), 1.61 (s, 3H).

Example 43:9-(4-(Aminomethyl)phenyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

tert-Butyl(4-((2-chloro-5-nitropyrimidin-4-yl)amino)benzyl)carbamate

To a stirred solution of 2, 4-dichloro-5-nitropyrimidine (0.5 g, 2 mmol)and DIPEA (1.34 mL, 8 mmol) in dioxane (20 mL) was addedtert-butyl(4-aminobenzyl)carbamate (0.63 g, 3 mmol) portionwise at 0° C.under nitrogen. The reaction mixture was slowly warmed to ambienttemperature and stirred for 1 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated to afford tert-butyl(4-((2-chloro-5-nitropyrimidin-4-yl)amino)benzyl)carbamate (0.9 g, 91%)as yellow solid. MS (ESI) m/z 380 [M+2]⁺.

tert-Butyl(4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)benzyl)carbamate

To a stirred solution of tert-butyl(4-((2-chloro-5-nitropyrimidin-4-yl)amino)benzyl)carbamate (0.9 g, 2mmol) in DMF (10 mL) was added 4-methyltetrahydro-2H-pyran-4-amine (0.3g, 2 mmol) and sodium bicarbonate (0.9 g, 11 mmol) at ambienttemperature. The reaction mixture was stirred for 5 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford tert-butyl(4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)benzyl)carbamate(0.95 g, 90%) as yellow solid. MS (ESI) m/z 459 [M+1]⁺.

tert-Butyl(4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)benzyl)carbamate

To a stirred solution of tert-butyl(4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)benzyl)carbamate(0.95 g, 2 mmol) in ethanol:water (50 mL, 3:1) was added iron powder(1.2 g, 20 mmol) and ammonium chloride (0.1 g, 2 mmol) at ambienttemperature. The reaction mixture was heated to 85° C. for 6 h.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through a bed of celite, washed with ethyl acetateand concentrated to affordtert-butyl(4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)benzyl)carbamate(0.92 g) as a brown solid. MS (ESI) m/z 430 [M+2]⁺.

tert-Butyl(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)benzyl)carbamate

To a stirred solution oftert-butyl(4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)benzyl)carbamate(0.95 g, 2 mmol) and 1-chloro-3-isothiocyanatobenzene (0.41 g, 2 mmol)in THF was added EDCI (0.85 g, 4 mmol) at ambient temperature. Thereaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and purifiedvia standard methods to afford tert-butyl (4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)benzyl)carbamate(0.5 g, 42%) as an off-white solid. MS (ESI) m/z 564, 566 [M, M+2]⁺.

9-(4-(Aminomethyl)phenyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl(4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9yl)benzyl)carbamate(0.180 g, 0.32 mmol) in DCM (20 mL) was added HCl in dioxane (5 mL) at0° C. The reaction mixture was stirred at ambient temperature for 4 h.Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford9-(4-(aminomethyl)phenyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(120 mg, 81%). MS (ESI) m/z 464.2, 465.2 [M, M+1]⁺. ¹H NMR (400 MHz,CD₃OD): δ8.31 (s, 1H), 7.75 (s, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.62 (d,J=8.4 Hz, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.26-7.30 (m, 1H), 7.03 (d, J=8.0Hz, 1H), 4.15 (s, 2H), 3.64-3.72 (m, 4H), 1.93-2.23 (m, 2H), 1.58-1.65(m, 2H), 1.40 (s, 3H).

Example 44: N8-(3-Chlorophenyl)-9-((1S, 4S)-4-((methylamino) methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

tert-Butyl (((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate

To a solution of 9-((1S,4S)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine(0.5 g, 1.06 mmol) in dry chloroform (10 mL) was addeddi-tert-butyldicarbonate (0.25 g, 1.17 mmol) at 0° C. and the reactionwas stirred for 3 h. Completion of the reaction was confirmed by UPLC.The product was isolated to afford tert butyl (((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate(0.5 g, 83%) as white solid. MS (ESI) m/z 570, 571 [M, M+1]⁺.

N8-(3-Chlorophenyl)-9-((1S,4S)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine

To a stirred solution of tertbutyl (((1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate(0.5 g, 0.88 mmol) in THF (10 mL) was added dropwise lithium aluminumhydride in THF (1.6 M, 5 mL) at 0° C. and heated at 50° C. for 8 h.Completion of the reaction was confirmed by UPLC. The product waspurified via standard methods to afford N8-(3-chlorophenyl)-9-((1S,4S)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine (24 mg, 6%). MS (ESI) m/z 484, 485 [M, M+1]+. ¹H NMR (400 MHz,CD₃OD): δ 8.20 (s, 1H), 7.92 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.36-7.40(m, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.48-4.54 (m, 1H), 3.80-3.83 (m, 4H),3.28 (d, J=6.8 Hz, 2H), 2.82 (s, 3H), 2.47-2.59 (m, 4H), 2.26 (brs, 1H),1.93-2.00 (m, 6H), 1.77-1.84 (m, 2H), 1.67 (s, 3H).

Example 45: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((2-(tert-Butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1 g, 3.3 mmol) in DMF (10 mL) was added tert-butylamine (0.3 g, 4 mmol)and sodium bicarbonate (0.84 g, 10 mmol) at ambient temperature. Thereaction mixture was heated to 60° C. for 4 h. Completion of thereaction was confirmed by UPLC. The product was isolated and trituratedwith petroleum ether to afford (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 63%) as a yellow solid. MS (ESI) m/z 337 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution (1S,4S)-4-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.7 g, 2 mmol) in ethanol (24 mL) was added palladium on carbon (0.1 g,W/W) under inert atmosphere at ambient temperature. The reaction mixturewas stirred under atmospheric hydrogen at ambient temperature.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard methods to afford (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 90%) as a brown solid. MS (ESI) m/z 307 [M+1]⁺.

(1S,4S)-4-(2-(tert-Butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) and 1-isothiocyanato-4-(trifluoromethyl)benzene (0.5 g,2 mmol) in THF (15 mL) was added EDCI (0.75 g, 4 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-(tert-butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-7,8-dihydro-9H-purin-9-yl)cyclohexane-1-carboxamide(0.45 g, 48%) as a yellow solid. MS (ESI) m/z 476 [M+1]⁺.

(1S,4S)-4-(2-(tert-Butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile

To a stirred solution of (1S,4S)-4-(2-(tert-butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.5 g, 1 mmol) in pyridine (5 mL) was added imidazole (0.2 g, 3 mmol)at 0° C. followed by dropwise addition of phosphorous oxychloride (0.5mL). The reaction mixture was stirred at ambient temperature for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-(tert-butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.25 g, 52%) as an off-white solid. MS (ESI) m/z 458 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-(tert-butylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.25 g, 1 mmol) in THF (10 mL) was added lithium aluminium hydride (1.6M in THF, 5 mL) dropwise at 0° C. The reaction mixture stirred atambient temperature for 3 h. Completion of the reaction was confirmed byUPLC. The product was purified via standard methods to afford 9-((1S, 4S)-4-(aminomethyl)cyclohexyl)-N2-(tert-butyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.045 g, 18%). MS (ESI) m/z 462 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.20(s, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.34-4.40 (m,1H), 3.04-3.06 (m, 2H), 2.71-2.80 (m, 2H), 1.91-2.01 (m, 4H), 1.75-1.85(m, 3H), 1.55 (s, 9H).

Example 46: 9-((1S,4S)-4-((Dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

tert-Butyl ((1S, 4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate

To a solution of (1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (2 g,8.2 mmol) in dry DCM (30 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g, 16 mmol), HOBt(1.1 g, 16 mmol), DIPEA (2.12 g, 33 mmol) and dimethyl amine (1.35 g, 33mmol, 2.4M solution in THF) at 0° C. The reaction mixture was stirred atambient temperature for 16 h. Completion of the reaction was confirmedby TLC. The product was isolated via standard purification methods toafford tert-butyl ((1S, 4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate (2g, 90%) as gummy solid. GCMS m/z 270 [M]⁺.

(1S, 4S)-4-Amino-N, N-dimethylcyclohexane-1-carboxamide

To a stirred solution of tert-butyl ((1S,4S)-4-(dimethylcarbamoyl)cyclohexyl)carbamate (2 g, 8 mmol) in ethanol(10 mL) was added dropwise to HCl in 1, 4-dioxane (4.5 M, 5 mL) at 0° C.The reaction mixture was stirred at ambient temperature for 4 h.Completion of the reaction was confirmed by TLC. The product wasisolated and purified via standard purification methods to afford (1S,4S)-4-amino-N,N-dimethylcyclohexane-1-carboxamide (1.2 g, 80%) as whitesolid. GCMS m/z 170 [M]⁺.

(1S,4S)-4-((2-Chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-amino-N,N-dimethylcyclohexane-1-carboxamide (1.9 g, 10 mmol) in IPA (30 mL) wasadded 2,4-dichloro-5-nitropyrimidine (1.9 g, 10 mmol) and DIPEA (3.7 g,30 mmol) at ambient temperature. The reaction mixture temperature wasraised to 50° C. and maintained for 2 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated via standard purificationmethods to afford (1S, 4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide (1 g, 30%). MS (ESI) m/z 327, 328[M, M+1]⁺.

(1S,4S)—N,N-Dimethyl-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.28 g, 2 mmol) in DMF (10 mL) was added 4-methyltetrahydro-2H-pyran-4-amine (0.5 g, 2 mmol), sodium carbonate (0.5 g, 5mmol). The reaction was stirred at ambient temperature for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated via standard purification method to afford (1S,4S)—N,N-dimethyl-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.23 g, 37%) as a pale brown solid MS (ESI) m/z 407 [M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide

To a stirred solution of (1S,4S)—N,N-dimethyl-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.23 g, 1 mmol) in ethanol (10 mL) was addedpalladium on carbon (30 mg, 10% W/M) under argon atmosphere. Thereaction mixture was stirred at ambient temperature under atmospherichydrogen. Completion of the reaction was confirmed by UPLC. The productwas isolated by standard purification methods to afford (1S,4S)-4-((5-amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.2 g, 90%) as violet solid MS (ESI) m/z 377 [M+1]⁺.

(1S, 4S)—N,N-Dimethyl-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

A solution of (1S,4S)-4-((5-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide(0.5 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.5 g,2.6 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.3 g, 1.6mmol) in THF (5 mL) were mixed at ambient temperature. The reaction washeated to 50° C. for 4 h. Completion of the reaction was confirmed byUPLC. The product was isolated by standard purification methods toafford (1S,4S)—N,N-dimethyl-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 48%) as an off-white solid MS (ESI) m/z 545, 546 [M, M+1]⁺.

9-((1S,4S)-4-((Dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution (1S,4S)—N,N-dimethyl-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.35 g, 0.64 mmol) in THF (3 mL) was added lithium aluminium hydride inTHF (1.6 M; 4 mL) at 0° C. The reaction was stirred at ambienttemperature for 1 h. Completion of the reaction was confirmed by TLC.The reaction mixture was quenched with 10% NaOH solution and water (10mL, 1:1) and extracted with ethyl acetate. The product was isolated bystandard methods to afford 9-((1S,4S)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.060 g, 33%). MS (ESI) m/z 532.4, 533.4 [M, M+1]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 9.22 (s, 1H), 8.31 (s, 1H, NH proton), 8.15 (s, 1H), 8.10(d, J=8.3 Hz, 1H), 7.54-7.58 (m, 1H), 7.30 (d, J=7.0 Hz, 1H), 6.35 (s,1H), 4.32-4.38 (m, 1H), 3.57-3.70 (m, 4H), 2.34-2.37 (m, 2H), 2.26-2.30(m, 2H), 2.19 (s, 6H), 2.00-2.15 (m, 1H), 1.85 (brs, 1H), 1.83-1.86 (m,2H), 1.62-1.70 (m, 7H), 1.50 (s, 3H).

Example 47: 9-((1S,4S)-4-((Methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

tert-Butyl(((1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethylphenyl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate

To a solution of 9-((1S, 4S)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.5 g, 0.99 mmol) in dry chloroform (10 mL) was addeddi-tert-butyldicarbonate (0.22 g, 0.99 mmol) at 0° C. and the reactionwas stirred for 3 h. Completion of the reaction was confirmed by TLC.The product was isolated to afford tert-butyl(((1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate(0.4 g, 67%) as a white solid. MS (ESI) m/z 604.2, 605.2 [M, M+1]⁺.

9-((1S,4S)-4-((Methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of tert-butyl (((1S,4S)-4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexyl)methyl)carbamate (0.4 g, 0.66 mmol) in diethyl ether (10 mL)was added dropwise LiAlH4 in THF (2 M; 4 mL) at 0° C. The reactionmixture was stirred at ambient temperature for 12 h. Completion of thereaction was confirmed by TLC. The product was purified via standardmethods to afford 9-((1S,4S)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.025 g; 7%). MS (ESI) m/z 518.4, [M+1]⁺. ¹HNMR (400 MHz, CD₃OD): δ8.23 (s, 1H), 7.95 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.51-7.55 (m, 1H),7.3 (d, J=7.3 Hz, 1H), 4.36 (brs, 1H), 3.77-3.78 (m, 4H), 2.95-2.96 (m,1H), 2.68-2.71 (m, 2H), 2.56 (brs, 2H), 2.34-2.38 (m, 2H), 1.96-2.03 (m,4H), 1.76-1.83 (m, 7H), 1.63 (s, 3H).

Example 48: 9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-pentyl)-N8-(4(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

(1S,4S)-4-((5-Nitro-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 2 mmol) in DMF (10 mL) was added sodium bicarbonate (0.17 g, 2mmol) portionwise followed by 2-methylbutane-2-amine (0.22 g, 2 mmol) atambient temperature. The reaction mixture was heated to 60° C. for 16 h.Completion of the reaction was confirmed by UPLC. The product wasisolated to afford (1S,4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl) amino)cyclohexane-1-carboxamide (0.6 g, 83%) as a yellow solid. MS (ESI) m/z351 [M+1]⁺.

(1S,4S)-4-8-((3-Chlorophenyl)amino-2-(tert-pentylamino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((5-nitro-2-(tert-pentylamino)pyrimidin-4-yl) amino)cyclohexane-1-carboxamide (0.5 g, 2 mmol) inethanol (10 mL) was added portionwise palladium on charcoal (0.06 g, 10%W/M) under an argon atmosphere. The reaction was stirred at ambienttemperature under atmospheric hydrogen. Completion of the reaction wasconfirmed by UPLC. The mixture was filtered through a bed of celite,washed with ethyl acetate and concentrated to afford (1S,4S)-4-8-((3-chlorophenyl)amino-2-(tert-pentylamino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.4 g, 90%) as a yellow solid. MS (ESI) m/z321 [M+1]⁺.

(1S,4S)-4-(2-(tert-Pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S, 4S)-4-((5-amino-2-(tert-pentylamino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g, 2 mmol) in THF(10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.6 g,3 mmol) and 1-isothiocyanato-4-(trifluoromethyl)benzene (0.3 g, 2 mmol)at ambient temperature. The reaction mixture was heated to 60° C. for 4h. Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(2-(tert-pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.45 g, 58%) as colorless solid. MS (ESI) m/z490 [M+1]⁺.

(1S,4S)-4-(2-(tert-Pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile

To a stirred solution of (1S,4S)-4-(2-(tert-pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide (0.25 g, 1 mmol) in pyridine (5 mL) was addedportionwise phosphorus oxychloride (0.5 ml) at 0° C. temperature. Thereaction mixture was stirred for 4 h. Completion of the reaction wasconfirmed by UPLC. The product was isolated and purified via standardmethods to afford (1S,4S)-4-(2-(tert-pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.2 g, 74%) as colorless solid. MS (ESI) m/z 472 [M+1]⁺.

9-((1S,4S)-4-(Aminomethyl)cyclohexyl)-N2-(tert-pentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine

To a stirred solution of (1S,4S)-4-(2-(tert-pentylamino)-8-((4-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.2 g, 1 mmol) in diethyl ether (3 mL) was added lithium aluminumhydride in THF (1.6 M; 2 mL) at 0° C. The reaction mixture was stirredat ambient temperature for 4 h. Completion of the reaction was confirmedby UPLC. The product was purified via standard methods to afford 9-((1S,4S)-4-(aminomethy)cyclohexyl)-N2-(tert-pentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine(0.03 g. 17%). MS (ESI) m/z 476 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.2(s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 4.33-4.40 (m,1H), 3.01 (d, J=7.2 Hz, 2H), 2.69-2.78 (m, 2H), 1.98-2.03 (m, 4H),1.74-1.89 (m, 5H), 1.50 (s, 6H), 0.93 (t, J=7.2 Hz, 3H).

Example 49:4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile

(1S,4S)-4-((2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To the stirred solution of (1S,4S)-4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(3.0 g, 9.24 mmol) in DMF (20 mL) was added4-methyltetrahydro-2H-pyran-4-amine (2.10 g, 13.86 mmol) and sodiumbicarbonate (3.0 g, 28 mmol) at ambient temperature and the mixture washeated to 60° C. for 16 h. Completion of the reaction was confirmed byTLC. The product was isolated to afford (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(1.5 g, 43%) as off-white solid. MS (ESI) m/z 379, 380 [M, M+1]⁺.

(1S,4S)-4-((5-Amino-2-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.6 g, 1.59 mmol) in methanol (10 mL) was added palladium on carbon(0.15 g) under inert atmosphere at ambient temperature. The reactionmixture was stirred under atmospheric hydrogen at ambient temperature.Completion of the reaction was confirmed by UPLC. The resulting reactionmixture was filtered through bed of celite, washed with methanol andconcentrated to afford (1S,4S)-4-((5-amino-2-((1-methylcyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g) as brown gummy solid. MS (ESI)m/z 349 [M]⁺.

(1S,4S)-4-(8-((3-Chlorophenyl)amino)-2-((1-methylcyclopentyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide

To a stirred solution of (1S,4S)-4-((5-amino-2-((1-methylcyclopentyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide(0.5 g, 1.44 mmol) and 1-isothiocyanato-3-(trifluoromethyl)benzene (0.35g, 1.72 mmol) in THF was added EDCI (0.82 g, 4.31 mmol) at ambienttemperature. The reaction mixture was heated to 60° C. for 4 h.Completion of the reaction was confirmed by UPLC. The product wasisolated and purified via standard methods to afford (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclopentyl)amino)-9H-purin-9-yl) cyclohexane-1-carboxamide (0.3 g, 41%) asoff-white solid. MS (ESI) m/z 519 [M+1]⁺.

4-(2-((4-Methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile

To a stirred solution (1S,4S)-4-(8-((3-chlorophenyl)amino)-2-((1-methylcyclopentyl)amino)-9H-purin-9-yl)cyclohexane-1-carboxamide(0.24 g, 0.51 mmol) in pyridine (2 mL) was added imidazole (0.03 g,0.46) at 0° C. POCl₃ (0.5 mL) was added dropwise at room temperature.The reaction mixture was stirred at ambient temperature for 2 h.Completion of the reaction was confirmed by TLC. The product waspurified via standard methods to afford4-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-8-((3-(trifluoromethyl)phenyl)amino)-9H-purin-9-yl)cyclohexane-1-carbonitrile(0.15 g, 78%). MS (ESI) m/z 500, 501 [M, M+1]+. ¹H NMR (400 MHz, CD₃OD):δ 8.22 (s, 1H), 8.08 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.54-7.58 (m, 1H),7.38 (d, 1H, J=8 Hz), 4.40-4.46 (m, 1H), 3.74-3.77 (m, 4H), 3.23 (brs,1H), 2.80-2.89 (m, 2H), 2.21-2.24 (m, 4H), 1.88-2.03 (m, 6H), 1.66 (s,3H).

In Vitro Parasite Growth Assays

In Vitro Alamar Blue 72 Hrs Drug Sensitivity Assay for T. Congolense.

Compounds were tested in vitro for chemotherapeutic efficacy against theIL3000 T. congolense (drug sensitive) strain using an Alamar Blue assay.Test compounds were prepared as 10 mg/mL DMSO stocks for each assay run.Compounds were assayed in at least three separate, independent test runsand an 11-point dilution curve was used to determine the IC₅₀ values.Bloodstream form trypanosomes were supported in HMI media containing 20%bovine serum and were incubated with test compounds for 69 hrs at 34° C.in a humidified atmosphere containing 5% CO₂. Thereafter, 10 μL ofResazurin dye (12.5 mg in 100 mL of phosphate buffered saline,Sigma-Aldrich, Buchs, Switzerland) were added for an additional 3 hrs.Plates were then read using a fluorescent plate reader (Spectramax,Gemini XS, Bucher Biotec, Basel, Switzerland) using an excitationwavelength of 536 nm and an emission wavelength of 588 nm. Data pointswere averaged to generate sigmoidal dose-response curves and IC₅₀ valueswere determined using Softmax Pro 5.2 software.

Ex vivo Alamar Blue48 hrs drug sensitivity assay for T. vivax.

Compounds were tested ex vivo for chemotherapeutic efficacy against theSTIB 719/ILRAD 560 T. vivax (drug sensitive) strain, using an AlamarBlue assay. Test compounds were prepared as 10 mg/mL DMSO stocks foreach assay run. Compounds were assayed in at least three separate,independent test runs and an 11-point dilution curve was used todetermine the IC₅₀ values. Bloodstream form trypanosomes were propagatedand harvested from a highly parasitaemic mouse (via cardiac puncture)and were incubated with test compounds for 45 hrs at 37° C. in ahumidified atmosphere containing 5% CO₂, supported in HMI mediacontaining 20% bovine serum. Thereafter, 10 μL of Resazurin dye (12.5 mgin 100 mL of phosphate buffered saline, Sigma-Aldrich, Buchs,Switzerland) were added for an additional 3 hrs. Plates were then readusing a fluorescent plate reader (Spectramax, Gemini XS, Bucher Biotec,Basel, Switzerland) using an excitation wavelength of 536 nm and anemission wavelength of 588 nm. Data points were averaged to generatesigmoidal dose-response curves and IC₅₀ values were determined usingSoftmax Pro 5.2 software.

In vitro Alamar Blue 72 hrs drug sensitivity assay for T. evansi.

Compounds were tested in vitro for chemotherapeutic efficacy against theSTIB 806 K T. evansi (drug sensitive) strain, using an Alamar Blueassay. Test compounds were prepared as 10 mg/mL DMSO stocks for eachassay run. Compounds were assayed in at least three separate,independent test runs and an 11-point dilution curve was used todetermine the IC₅₀ values. Bloodstream form trypanosomes were incubatedwith test compounds for 69 hrs at 37° C. in a humidified atmospherecontaining 5% CO₂, supported in HMI media containing 15% horse serum.Thereafter, 10 μL of Resazurin dye (12.5 mg in 100 mL of phosphatebuffered saline, Sigma-Aldrich, Buchs, Switzerland) were added for anadditional 3 hrs. Plates were then read using a fluorescent plate reader(Spectramax, Gemini XS, Bucher Biotec, Basel, Switzerland) using anexcitation wavelength of 536 nm and an emission wavelength of 588 nm.Data points were averaged to generate sigmoidal dose-response curves andIC₅₀ values were determined using Softmax Pro 5.2 software.

In Vitro Alamar Blue 72 Hrs Drug Cytotoxicity Assay.

Compounds were tested in vitro for cytotoxicity against the rat myoblast(L6) cell line, using an Alamar Blue assay. Test compounds were preparedas 10 mg/mL DMSO stocks for each assay run. Compounds were assayed in atleast three separate, independent test runs and an 11-point dilutioncurve was used to determine the IC₅₀ values. The L6 cells were seededand allowed to attach to the plates overnight, before the compounds wereapplied. The L6 cells were incubated with test compounds for 69 hrs at37° C. in a humidified atmosphere containing 5% CO₂, supported in RPMImedia containing 10% fetal calf serum. Thereafter, 10 μL of Resazurindye (12.5 mg in 100 mL of phosphate buffered saline, Sigma-Aldrich,Buchs, Switzerland) were added for an additional 3 hrs. Plates were thenread using a fluorescent plate reader (Spectramax, Gemini XS, BucherBiotec, Basel, Switzerland) using an excitation wavelength of 536 nm andan emission wavelength of 588 nm. Data points were averaged to generatesigmoidal dose-response curves and IC₅₀ values were determined usingSoftmax Pro 5.2 software.

Activity Table

Each of the compounds in Table 1 and Table 2 was tested in at least oneof the in vitro parasite growth assays and was found to have activitytherein, with all of the Aminopurine Compounds of Formula (I) having anIC₅₀ below or at 0.5 μM in the assay, with some compounds having an IC₅₀between 0.5 μM and 0.35 μM (activity level A), some an IC₅₀ between 0.15μM and 0.35 μM (activity level B), and some an IC₅₀ below 0.15 μM(activity level C).

TABLE 1 Cpd T. congo T. vivax T. evansi #A- Structure Name MH+ Act. Act.Act. 1

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 471.2 C C C 2

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(1-methylcyclobutyl)-9H- purine-2,8-diamine 440.2 C C 3

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-tert-pentyl-9H-purine-2,8- diamine 442.2 C C 4

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(1-methylcyclopentyl)-9H- purine-2,8-diamine 454.2 C C C 5

N8-(3-chlorophenyl)-9- ((1s,4s)-4- ((dimethylamino)methyl)cyclohexyl)-N2-(4- methyltetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 498.4 C C C 6

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-(pyridin-2-yl)-9H- purine-2,8-diamine 395.2 A C 7

9-((1r,4r)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 470.2 C C C 8

9-((1s,4s)-4- (aminomethyl)cyclohexyl)- N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8- (pyridin-2-yl)-9H- purine-2,8-diamine 437.2 A B 9

9-((1s,4s)-4- (aminomethyl)cyclohexyl)- N8-(2,3- difluorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 472.2 C C 10

(1s,4s)-4-(8-(3- chlorophenylamino)-2- (1- methylcyclopentylamino)-9H-purin-9- yl)cyclohexanol 441.2 A A 11

N-(((1s,4s)-4-(8-(3- chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)methyl) acetamide 512.2 AC A 12

9-((1s,4s)-4- (aminomethyl)cyclohexyl)- N2-(1- methylcyclopentyl)-N8-(3- (trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 488.2 A B 13

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-pentyl-N8- (3-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 476.4 C C C 14

methyl ((1s,4s)-4-(8-(3- chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)methylcar bamate 528.2 BA 15

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 462.2 C C 16

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(1- methylcyclopentyl)-N8-(4- (trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 489.4 A A 17

9-((1r,4r)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 462.2 C C 18

9-((1r,4r)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-p-tolyl-9H-purine-2,8- diamine 408.4 A B 19

((1s,4s)-4-(8-(3- chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)methanol 471.2 A B 20

9-((1R,3S)-3- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 470 A C 21

N8-(3-chlorophenyl)-9- ((1s,4s)-4- ((methylamino)methyl)cyclohexyl)-N2-(4- methyltetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 484 C C 22

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 462 B A 23

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-pentyl-N8- (4-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 476 A A 24

(1s,4s)-4-(2-(4- methyltetrahydro-2H- pyran-4-ylamino)-8-(3-(trifluoromethyl)phenyl amino)-9H-purin-9- yl)cyclohexanecarbonitrile500 B B 25

N-((1s,4s)-4-(8-(3- chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)acetamide 498.2 A C 26

((1r,4r)-4-(8-(3- chlorophenylamino)-2- (4-methyltetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)methanol 471.2 B C 27

9-((1s,4s)-4- aminocyclohexyl)-N8- (3-chlorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 456.2 C C 28

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8-(3- (trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 504.2C C C 29

9-((1s,4s)-4- aminocyclohexyl)-N2- tert-butyl-N8-(3-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 448.2 C C 30

9-((1r,4r)-4- aminocyclohexyl)-N2- tert-butyl-N8-(3-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 448.2 C C 31

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8-(4- (trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 504.2B C 32

9-(4- (aminomethyl)phenyl)- N8-(3-chlorophenyl)- N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 464.2 B C 33

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(5- chloropyridin-3-yl)-N2-(4-methyltetrahydro- 2H-pyran-4-yl)-9H- purine-2,8-diamine 471.2 B C 34

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8-(2- (trifluoromethyl)pyridin- 4-yl)-9H-purine-2,8-diamine 505.2 C C C 35

9-(3-aminocyclobutyl)- N8-(3-chlorophenyl)- N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine- 2,8-diamine 428.2 C C 36

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)- N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine- 2,8-diamine 538.2 C C B 37

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8-(3- (trifluoromethoxy)phen yl)-9H-purine-2,8- diamine520.2 C C C 38

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahdro-2H-pyran-4-yl)-N8-(4- (trifluoromethoxy)phen yl)-9H-purine-2,8- diamine520.2 C C B 39

9-(3-aminocyclobutyl)- N2-tert-butyl-N8-(3,4- dichlorophenyl)-9H-purine-2,8-diamine 420.2 A B 40

N8-(3-chlorophenyl)- N2-(4- methyltetrahydro-2H- pyran-4-yl)-9-((1s,4s)-4-(piperidin-1- ylmethyl)cyclohexyl)- 9H-purine-2,8-diamine 538.2 C C C41

N8-(3-chlorophenyl)- N2-(4- methyltetrahydro-2H- pyran-4-yl)-9-((1s,4s)-4- (morpholinomethyl)cyclo- hexyl)-9H-purine-2,8- diamine 540.2 C A 42

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)- N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine- 2,8-diamine 522.2 C C 43

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3,5- dichlorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 504.2 C C C 44

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3,5- difluorophenyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H-purine- 2,8-diamine 472.2 C C C 45

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(4- methyltetrahydro-2H-pyran-4-yl)-N8-(6- (trifluoromethyl)pyridin- 2-yl)-9H-purine-2,8-diamine 503.2 (M − H); 505.2 B B 46

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)- N2-(4- methyltetrahydro-2H-pyran-4-yl)-9H-purine- 2,8-diamine 522.2 C C C 47

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4- methyltetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 488.2 C C C 48

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-tert-butyl-N8-(3,5-dichlorophenyl)- 9H-purine-2,8-diamine 462.2 B A 49

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4- methyltetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 488.2 C C C 50

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(4- methyltetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 488.2 C C 51

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3- chlorophenyl)-N2-(1-methylcyclopropyl)-9H- purine-2,8-diamine 426.2 C C 52

3-(9-((1r,4r)-4- aminocyclohexyl)-2- (tert-butylamino)-9H- purin-8-ylamino)benzonitrile 405.4 A C 53

9-((1r,4r)-4- aminocyclohexyl)-N2- tert-butyl-N8-(3-chloro- 5-(trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 482.2 B B 54

2-(9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-8-(3- chlorophenylamino)-9H-purin-2-ylamino)-2- methylpropan-l-ol 444.2 B C 55

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)- N2-(1- methylcyclobutyl)-9H-purine-2,8-diamine 508.2 B A 56

9-((1s,4s)-4- ((dimethylamino)methyl) cyclohexyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-N8-(3- (trifluoromethyl)phenyl)-9H-purine-2,8-diamine 532.4 C C 57

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N2-(1- methylcyclobutyl)-N8-(3- (trifluoromethyl)phenyl)- 9H-purine-2,8-diamine 473.2 C 58

9-((1s,4s)-4- ((methylamino)methyl) cyclohexyl)-N2-(4-methyltetrahydro-2H- pyran-4-yl)-N8-(3- (trifluoromethyl)phenyl)-9H-purine-2,8- diamine 518.4 C C 59

9-(4- aminocyclohexyl)-N8- (2-fluoro-5- (trifluoromethyl)phenyl)- N2-(4-methyltetrahydro-2H- pyran-4-yl)-9H- purine-2,8-diamine 508.2 B C 60

N2-tert-butyl-N8-(3- chloro-2- fluorophenyl)-9- ((1s,4s)-4-((dimethylamino)meth yl)cyclohexyl)-9H- purine-2,8-diamine 475.2 C C 61

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)- N2-(1- methylcyclobutyl)-9H-purine-2,8-diamine 492.2 B C

TABLE 2 Cpd T. congo T. vivax T. evansi #B- Structure Name MH+ Act. Act.Act. 1

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2-(tetrahydro-2H- pyran-4-yl)-9H- purine-2,8-diamine 456.2 B A 2

9-((1r,4r)-4- aminocyclohexyl)- N8-(3- chlorophenyl)-N2- cyclopropyl-9H-purine-2,8-diamine 368.2 A C 3

9-((1r,4r)-4- aminocyclohexyl)- N8-(3- chlorophenyl)-N2-(cyclopropylmethyl)- 9H-purine-2,8- diamine 412.2 A A 4

9-((1r,4r)-4- aminocyclohexyl)- N8-(3- chlorophenyl)-N2- (2,2,2-trifluoroethyl)-9H- purine-2,8-diamine 440.2 A C 5

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2-methyl-N2- (tetrahydro-2H- pyran-4-yl)-9H- purine-2,8-diamine 470 A C 6

((1s,4s)-4-(8-(3- chlorophenylamino)- 2-(tetrahydro-2H-pyran-4-ylamino)- 9H-purin-9- yl)cyclohexyl)meth anol 457 A A 7

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2,N2-dimethyl- 9H-purine-2,8- diamine 400.2 A C 8

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2- (2,2-dimethyltetrahydro- 2H-pyran-4-yl)-9H- purine-2,8-diamine 484.2 B C 9

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2-methyl-9H-purine- 2,8-diamine 386.2 A C 10

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chlorophenyl)-N2- (2,2,2-trifluoroethyl)-9H- purine-2,8-diamine 454.2 A C 11

4-(9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-8-(3- chlorophenylamino)-9H-purin-2- ylamino)-1- methylcyclohexanol 484.4 A C 12

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chloro-5-(trifluoromethyl)phe nyl)-N2- (tetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 524.2 A A 13

9-((1s,4s)-4- (aminomethyl)cyclo hexyl)-N8-(3- chloro-2-fluorophenyl)-N2- (tetrahydro-2H- pyran-4-yl)-9H- purine-2,8-diamine474.2 C 14

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(2- fluoro-5-(trifluoromethyl) phenyl)-N2,N2- dimethyl-9H- purine-2,8-diamine 452.2 AC 15

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N-(2- fluoro-5-(trifluoromethyl) phenyl)-2- (pyrrolidin-l-yl)- 9H-purin-8-amine 478.2 BC 16

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(2- fluoro-5-(trifluoromethyl) phenyl)-N2- (tetrahydro-2H- pyran-4-yl)-9H-purine-2,8-diamine 508.2 A C 17

9-((1s,4s)-4- (aminomethyl)cyclo- hexyl)-N8-(5- chloro-2-fluorophenyl)-N2- (tetrahydro-2H- fluorophenyl)-N2- pyran-4-yl)-9H-purine-2,8-diamine 475.2 C C

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A method for the treatment or prevention oftrypanosomosis, trypanosomiasis, or leishmaniasis, the method comprisingadministering to a subject having trypanosomosis, trypanosomiasis, orleishmaniasis an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, wherein: R¹ is CR^(1a)R^(1b)R^(1c), wherein eachof R^(1a), R^(1b) and R^(1c) is independently (C₁₋₄)alkyl, or(C₁₋₄)alkyl(OR); or R^(1a) and R^(1b) and the carbon to which they areattached form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl,and R^(1c) is (C₁₋₄)alkyl; R² is cycloalkyl or aryl, substituted with atleast one NR₂, OR, CN, NRC(O)R, CH₂OR, CH₂NR₂, CH₂NRCOR, CH₂NRCOOR′, orheterocyclylalkyl; R³ is phenyl or pyridyl, optionally substituted withat least one halogen, CN, (C₁₋₂)alkyl, or O(C₁₋₂)alkyl, wherein thealkyl is optionally fluorinated; R is H or (C₁₋₄) alkyl; and R′ is(C₁₋₄)alkyl.
 2. The method of claim 1, wherein R¹ isCR^(1a)R^(1b)R^(1c), wherein each of R^(1a), R^(1b) and R^(1c) isindependently (C₁₋₂)alkyl.
 3. The method of claim 1, wherein R¹ ist-butyl, C(CH₃)₂CH₂CH₃, or C(CH₃)₂CH₂OH.
 4. The method of claim 1,wherein R¹ is CR^(1a)R^(1b)R^(1c), and wherein R^(1a) and R^(1b) and thecarbon to which they are attached form a 3-6 membered cycloalkyl or 3-6membered heterocyclyl, and R^(1c) is (C₁₋₄)alkyl.
 5. The method of claim4, wherein R^(1a) and R^(1b) and the carbon to which they are attachedform a cyclopropyl, cyclobutyl, cyclohexyl, or tetrahydropyranyl.
 6. Themethod of claim 4, wherein R^(1c) is CH₃.
 7. The method of claim 1,wherein R¹ is 1-methylcyclopropyl, 1-methylcyclobutyl,1-methylcyclpentyl or 1-methyl-tetrahydropyranyl.
 8. The method of claim1, wherein R² is (C₃₋₇)cycloalkyl, substituted with at least one NR₂,OR, CN, NRC(O)R, CH₂OR, CH₂NR₂, CH₂NRC(O)R, CH₂NRC(O)OR′ orheterocyclylalkyl.
 9. The method of claim 8, wherein R² is cyclobutyl,cyclopentyl, or cyclohexyl.
 10. The method of claim 8, wherein R² issubstituted with at least one NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, CN,NHC(O)CH₃, N(CH₃)C(O)CH₃, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂,CH₂NHC(O)CH₃, CH₂N(CH₃)C(O)CH₃, CH₂NHC(O)OCH₃, CH₂N(CH₃)C(O)OCH₃,CH₂-piperidyl, or CH₂-morpholinyl.
 11. The method of claim 8, wherein R²is cyclohexyl, substituted with NH₂, OH, CN, NHC(O)CH₃, CH₂OH, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂NHC(O)CH₃, CH₂NHC(O)OCH₃, CH₂-piperidyl, orCH₂-morpholinyl.
 12. The method of claim 1, wherein R² is aryl,substituted with at least one NR₂, OR, CN, NRC(O)R, CH₂OR, CH₂NR₂,CH₂NRCOR, or CH₂NRCOOR′.
 13. The method of claim 12, wherein R² isphenyl, substituted with at least one NH₂, NHCH₃, N(CH₃)₂, OH, OCH₃, CN,NHC(O)CH₃, N(CH₃)C(O)CH₃, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂,CH₂NHC(O)CH₃, CH₂N(CH₃)C(O)CH₃, CH₂NHC(O)OCH₃, or CH₂N(CH₃)C(O)OCH₃. 14.The method of claim 12, wherein R² is phenyl, substituted with CH₂NH₂.15. The method of claim 1, wherein R³ is phenyl substituted with atleast one halogen, fluorinated (C₁₋₂)alkyl, or O-fluorinated(C₁₋₂)alkyl.16. The method of claim 15, wherein R³ is substituted with at least oneF, Cl, CHF₂, CF₃, or OCF₃.
 17. The method of claim 15, wherein R³ ismeta-substituted phenyl.
 18. The method of claim 1, wherein R³ ispyridyl, substituted with at least one halogen, fluorinated (C₁₋₂)alkyl,or O-fluorinated(C₁₋₂)alkyl.
 19. The method of claim 18, wherein R³ issubstituted with at least one F, Cl, CHF₂, CF₃, or OCF₃.
 20. The methodof claim 18, wherein R³ is substituted with at least one Cl, or CF₃. 21.The method of claim 1, wherein the compound is:9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-tert-pentyl-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopentyl)-9H-purine-2,8-diamine,N8-(3-chlorophenyl)-9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(pyridin-2-yl)-9H-purine-2,8-diamine,9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(pyridin-2-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2,3-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,(1s,4s)-4-(8-(3-chlorophenylamino)-2-(1-methylcyclopentylamino)-9H-purin-9-yl)cyclohexanol,N-(((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methyl)acetamide,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,methyl((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methylcarbamate,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclopentyl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1r,4r)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-p-tolyl-9H-purine-2,8-diamine,((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol,9-((1R, 3S)-3-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,N8-(3-chlorophenyl)-9-((1s,4s)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-pentyl-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,(1s,4s)-4-(2-(4-methyltetrahydro-2H-pyran-4-ylamino)-8-(3-(trifluoromethyl)phenylamino)-9H-purin-9-yl)cyclohexanecarbonitrile,N-((1s,4s)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)acetamide,((1r,4r)-4-(8-(3-chlorophenylamino)-2-(4-methyltetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol,9-((1s,4s)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1r,4r)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-(4-(aminomethyl)phenyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloropyridin-3-yl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(2-(trifluoromethyl)pyridin-4-yl)-9H-purine-2,8-diamine,9-(3-aminocyclobutyl)-N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(4-(trifluoromethoxy)phenyl)-9H-purine-2,8-diamine,9-(3-aminocyclobutyl)-N2-tert-butyl-N8-(3,4-dichlorophenyl)-9H-purine-2,8-diamine,N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1s,4s)-4-(piperidin-1-ylmethyl)cyclohexyl)-9H-purine-2,8-diamine,N8-(3-chlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9-((1s,4s)-4-(morpholinomethyl)cyclohexyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3,5-dichlorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3,5-difluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(6-(trifluoromethyl)pyridin-2-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-3-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-tert-butyl-N8-(3,5-dichlorophenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(1-methylcyclopropyl)-9H-purine-2,8-diamine,3-(9-((1r,4r)-4-aminocyclohexyl)-2-(tert-butylamino)-9H-purin-8-ylamino)benzonitrile,9-((1r,4r)-4-aminocyclohexyl)-N2-tert-butyl-N8-(3-chloro-5-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,2-(9-((1s,4s)-4-(aminomethyl)cyclohexyl)-8-(3-chlorophenylamino)-9H-purin-2-ylamino)-2-methylpropan-1-ol,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N2-(1-methylcyclobutyl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-((methylamino)methyl)cyclohexyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-N8-(3-(trifluoromethyl)phenyl)-9H-purine-2,8-diamine,9-(4-aminocyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(4-methyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,N2-tert-butyl-N8-(3-chloro-2-fluorophenyl)-9-((1s,4s)-4-((dimethylamino)methyl)cyclohexyl)-9H-purine-2,8-diamine,or9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(1-methylcyclobutyl)-9H-purine-2,8-diamine,or a pharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof.
 22. A method for the treatment or prevention oftrypanosomosis, trypanosomiasis, or leishmaniasis, the method comprisingadministering to a subject having trypanosomosis, trypanosomiasis, orleishmaniasis an effective amount of a compound, wherein the compoundis:9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-cyclopropyl-9H-purine-2,8-diamine,9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(cyclopropylmethyl)-9H-purine-2,8-diamine,9-((1r,4r)-4-aminocyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2,2-trifluoroethyl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,((1s,4s)-4-(8-(3-chlorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexyl)methanol,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2,N2-dimethyl-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-methyl-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chlorophenyl)-N2-(2,2,2-trifluoroethyl)-9H-purine-2,8-diamine,4-(9-((1s,4s)-4-(aminomethyl)cyclohexyl)-8-(3-chlorophenylamino)-9H-purin-2-ylamino)-1-methylcyclohexanol,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-5-(trifluoromethyl)phenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(3-chloro-2-fluorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2,N2-dimethyl-9H-purine-2,8-diamine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-(pyrrolidin-1-yl)-9H-purin-8-amine,9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(2-fluoro-5-(trifluoromethyl)phenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,or9-((1s,4s)-4-(aminomethyl)cyclohexyl)-N8-(5-chloro-2-fluorophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-9H-purine-2,8-diamine,or a pharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof.
 23. The method of claim 1, wherein thetrypanosomosis or trypanosomiasis is caused by T. avium, T. boissoni, T.brucei, T. b. gambiense, T. b. rhodesiense, T. b. evansi, T. carassii,T. cruzi, T. congolense, T. equinum, T. equiperdum, T. evansi, T.godfreyi, T. hosei, T. levisi, T. melophagium, T. parroti, T. percae, T.rangeli, T. rotatorium, T. rugosae, T. sergenti, T. simiae, T.sinipercae, T. suis, T. theileri, T. triglae or T. vivax.
 24. The methodof claim 1, wherein the trypanosomosis is Animal trypanosomosis orAfrican animal trypanosomosis (AAT).
 25. The method of claim 24, furthercomprising the administration of a second active agent.
 26. The methodof claim 25, wherein the second active agent is at least one ofdiminazene di-aceturate, quinapyramine sulphate, melarsomine,isometamidium, homidium chloride or bromide.
 27. The method of claim 1,wherein the trypanosomiasis is Human African trypanosomiasis (HAT). 28.The method of claim 27, further comprising the administration of asecond active agent.
 29. The method of claim 28, wherein the secondactive agent is pentamidine, suramin, melarsoprol, eflornithine ornifurtimox.
 30. The method of claim 1, wherein the trypanosomiasis isAmerican trypanosomiasis or Chagas disease.
 31. The method of claim 30,further comprising the administration of a second active agent.
 32. Themethod of claim 31, wherein the second active agent is benznidazole ornifurtimox.
 33. The method of claim 1, wherein leishmaniasis is treatedor prevented.
 34. The method of claim 33, further comprising theadministration of a second active agent.
 35. The method of claim 34,wherein the second active agent is pentavalent antimonials, AmphotericinB deoxycholate, pentamidine, paromomycin sulfate, miltefosine orketoconazole.